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Gene therapy is being studied as a treatment for osteoarthritis (OA). Unlike pharmacological treatments which are administered systemically, gene therapy aims to establish sustained, synthesis of gene products and tissue rehabilitation within the joint.^[1]

The main risk factors for osteoarthritis are age^[2]^[3] and body mass index^[4]^[5], as such, OA is predominantly considered a disease of aging.^[6]^[7] As the body ages, catabolic factors begin to predominate over anabolic factors resulting in a reduction in extracellular matrix gene expression^[8] and reduced cellularity^[9]^[10] in articular cartilage. As a result, catabolism eventually predominates over anabolism to such an extent that severe cartilage erosions and bone marrow lesions / remodeling manifest in clinical osteoarthritis. In addition, osteoarthritis has a number of heritable factors, and there may be genetic risk factors for the disease.

Gene augmentation^[11] and gene therapy^[12] strategies for the potential medical management of osteoarthritis are under preliminary research to define pathological mechanisms and possible treatments for this chronic disease. While viral-vector based gene therapies predominate, both viral and non-viral vectors have been developed as a means to carry therapeutic genes and inject them into human cells.^[13]

Theory of Gene Augmentation approaches

As the body ages, catabolic factors begin to predominate over anabolic factors. In osteoarthritis, catabolic factors promote the degradation of articular cartilage and decrease the total cell content of cartilage.^[14] While anabolic factors are able to replace the lost cartilage and cartilage producing cells when the organism is young, this ability is decreased with age. Gene Augmentation approaches, such as the delivery of FGF18 and PRG4 aim to augment the anabolic processes to delay the progression of cartilage degeneration.^[11]^[15] Catabolic factors appear to be successful in clinical studies when delivered in the form of repeat protein injections, however, due to the pharmacokinetics of articular joints, these approaches require up to 12 injections per year in bilateral osteoarthritis, and may need to be sustained indefinitely to prevent reversal of cartilage gains.^[16] Gene Augmentation approaches aim to replicate the success of anabolic protein therapies by delivering the anabolic genetic instructions as a single injection treatment.^[11]

Theory of Gene Replacement / Gene Therapy approaches

Passing from parents to children, genes are the building blocks of inheritance. They contain instructions for making proteins. If genes do not produce the right proteins in a correct way, a child can have a genetic disorder. Gene therapy is a molecular method aiming to replace defective or absent genes, or to counteract the ones undergoing overexpression. For this purpose, three techniques may be utilized: gene isolation, manipulations, and transferring to target cells.^[17] The most common form of gene therapy involves inserting a normal gene to replace an abnormal gene. Other approaches including repairing an abnormal gene and altering the degree to which a gene is turned on or off. Two basic methodologies are utilized to transfer vectors into target tissues; Ex vivo gene transfer and In-vivo gene transfer. One type of gene therapy in which the gene transfer takes place outside the patient's body is called ex vivo gene therapy. This method of gene therapy is more complicated but safer since it is possible to culture, test, and control the modified cells.

Significance and causes of osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease which is the western world's leading cause of pain and disability.^[18]^[19] It is characterized by the progressive loss of normal structure and function of articular cartilage, the smooth tissue covering the end of the moving bones.^[20] This chronic disease not only affects the articular cartilage but the subchondral bone, the synovium and periarticular tissues are other candidates.^[18] People with OA can experience severe pain and limited motion. OA is mostly the result of natural aging of the joint due to biochemical changes in the cartilage extracellular matrix.^[19]^[21]

While age^[22]^[23] and BMI^[24] are the main risk factors for Osteoarthritis, contributors such as joint trauma and mechanical overloading of joints or joint-instability can accelerate or exacerbate the condition.^[1]^[21] Since the degeneration of cartilage is an irreversible phenomenon, it is incurable, costly and responds poorly to treatment.^[18] Due to the prevalence of this disease, the repair and regeneration of articular cartilage has become a dominant area of research.^[20] The growing number of the people suffering from osteoarthritis and the effectiveness of the current treatments attract a great deal of attention to genetic-based therapeutic methods to treat the progression of this chronic disease.

Vectors for osteoarthritis gene delivery

Various vectors have been developed to carry the therapeutic genes to cells. There are two broad categories of gene delivery vectors: Viral vectors, involving viruses and non-viral agents, such as polymers, lipid nanoparticles, and liposomes.^[1]^[25]

Viral vectors

Viral vectors are the most widely used gene delivery method as they have evolved to do this with a high degree of efficiency. When using viral vectors for gene delivery, researchers aim to remove all of the dangerous or pathogenic genes from the virus and replace them with at least one therapeutic gene. This makes the viral vectors highly effective at delivering the genetic cargo to cells, and significantly reduces the risks associated with using the viral vehicle.

When administered systemically, or in high doses, viral vectors can induce an inflammatory response, which can cause minor side effects such as edema or serious ones like multisystem organ failure.^[26] It may also be difficult to administer gene therapy repeatedly due to the immune system's enhanced response to viruses. However, viral vectors delivered locally to the joint, appear to be highly localized and well tolerated based on preclinical and early clinical studies.^[27]^[28]^[29] Furthermore, the durability of therapeutic transgene expression appears to be such, that a single injection therapy may be sufficient to reverse progression of a disease.^[30]

Non-viral vectors

Non-viral methods involve complexing therapeutic DNA to various macromolecules including cationic lipids and liposomes, polymers, polyamines and polyethylenimine, and nanoparticles.^[1] FuGene 6 ^[31] and modified cationic liposomes ^[32] are two non-viral gene delivery methods that have so far been utilized for gene delivery to cartilage. FuGene 6 is a non-liposomal lipid formulation, which has proved to be successful in transfecting a variety of cell lines. Liposomes have shown to be an appropriate candidate for gene delivery,^[33] where cationic liposomes are made to facilitate the interaction with the cell membranes and nucleic acids.^[34] Non-viral vectors may have the capacity to deliver a large amount of therapeutic genes repeatedly and may be lower cost to produce at large scale. Another advantage of non-viral delivery methods is that they do not elicit a memory immune response and may be administered several times. In spite of having advantages, non-viral vectors have not yet replaced viral vectors due to relatively low efficiency, toxicity, and short-term transgene expression.^[25] As a result, while a number of viral vectors have successfully been used in several clinical studies, non-viral vectors for intra-articular delivery have thus far only been investigated preclinically.

Target cells in osteoarthritis gene therapy

The cells targeted for the treatment of osteoarthritis are chondrocytes, synoviocytes, and their progenitors. Since the joint capsule is relatively well contained, intra-articular injections are highly successful at delivering the therapeutic gene therapy locally to the target cell types.

Treatment of osteoarthritis may be successful via:

Stimulation of anabolic pathways to rebuild the matrix or chondrocyte content - may result in reversal of the disease^[11]^[16] (Examples include: FGF18).
Inhibition of catabolic pathways - may result in slowing of the disease progression, but not reversal (Examples include: IL-1Ra).
Replacing of the damaged cells or tissues - may result in reversal of the disease pathology^[35] (Examples include: MACI and Hyalofast).
Avoiding the pathological or symptomatic complications such as the reduction of pain or formation of osteophytes^[36] (Examples include, steroids and viscosupplements).

Thus far, the most promising therapies appear to be those focused on promoting cartilage anabolism. Specifically, only the chondro-anabolic FGF18 therapy which uses the recombinant protein analog of FGF18, sprifermin, has been able to demonstrate an ability to increase cartilage thickness in a dose-dependent manner^[16], arrest progression to joint replacement^[16], and reduce pain and clinically-meaningful symptom progression.^[16]^[37] Based on this success, FGF18 is also being investigated as a gene therapy for the treatment of OA.^[11]

While several anti-inflammatory or anti-catabolic approaches have been reported in preclinical studies, none of the clinical studies to date have produced any evidence of efficacy. (IGF-I/IL-1RA),^[38].

Gene defects leading to osteoarthritis

While Osteoarthritis is mainly a disease of aging, it has some degree of heritability.^[39] Forms of osteoarthritis associated with genetic mutations may have an increased chance of treatment by gene therapy.^[18]

Epidemiological studies have shown that a genetic component may be an important risk factor in OA.^[40] Insulin-like growth factor I genes (IGF-1), Transforming growth factorβ, cartilage oligomeric matrix protein, bone morphogenetic protein, and other anabolic gene candidates are among the candidate genes for OA.^[25] Genetic changes in OA can lead to defects of a structural protein such as collagen, or changes in the metabolism of bone and cartilage. OA is rarely considered as a simple disorder following Mendelian inheritance being predominantly a multifactorial disease.

However, in the field of OA gene therapy, researches has focused on gene transfer as a delivery system for therapeutic gene products, rather counteracting genetic abnormalities or polymorphisms. Genes, which contribute to protect and restore the matrix of articular cartilage, are attracting the most attention. These Genes are listed in Table 1. Among all candidates listed below, only FGF18 has been successful at a protein level in initial clinical studies.^[16] Other candidates, such as proteins that block the actions of interleukin-1 (IL-1) (interleukin-1 receptor antagonists / IL-1Ra) have been evaluated as both protein or gene therapy injections and were either abandoned (as in the case of the protein) or did not report any efficacy.

**Table 1- Candidates for OA gene therapy** ^[18]^[41]
Category	Gene Candidate
Promotes cartilage formation	FGF18
Cytokine/cytokine antagonist	IL-1Ra, sIL-1R, sTNFR, IL-4
Cartilage growth factor	IGF-1, FGF, BMPs, TGF, CGDF
Matrix breakdown inhibitor	TIMPs, PAIs, serpins
Signaling molecule/transcription factor	Smad, Sox-9, IkB
Apoptosis Inhibitor	Bcl-2
Extra cellular matrix molecule	Type II collagen, COMP
Free radical antagonist	Super Oxide Dismutase

FGF18 as a target in osteoarthritis

To date, the most promising preclinical evidence and clinical trial results have been derived from trials using FGF18 protein or FGF18 gene therapy. Delivered as a protein, sprifermin (FGF18 analog), was able to increase cartilage thickness in a dose dependent manner in placebo controlled, randomized clinical studies.^[16] A result never previously achieved in osteoarthritis clinical history. The trial also demonstrated the potential of FGF18 to completely arrest progression to joint replacement over the study period. Finally, FGF18 was able to reduce pain (WOMAC) and clinically-meaningful symptom progression, in both the full trial population and the high-risk subgroup.^[16]^[37] Based on these highly promising clinical results, FGF18 is being investigated as a gene therapy for the treatment of osteoarthritis.^[11]

Interleukin-1 as a target in osteoarthritis

While preclinical studies suggest that an anti-inflammatory Interleukin-1 is a contributor to joint pain, cartilage loss, and inflammation, none of these findings have been confirmed in clinical studies.^[42] A therapeutic gene with potential to counteract the effect of interleukin-1^[43], the Interleukin 1 receptor antagonist (IL-1Ra), is currently being evaluated in early clinical trials with several delivery vectors including AAV and adenovirus. The natural agonist of IL-1, is a protein that binds non-productively to the cell surface of interleukin-1 receptor, blocking the activity of IL-1 via the IL-1 receptor.^[44]^[45] A number of studies in dogs, rabbits, and horses suggested that local IL-1Ra gene therapy is safe and effective in animal models of OA^[46]^[47]^[48], however, none of these findings have translated to clinical efficacy despite both the protein and gene therapy being evaluated in multiple clinical trials.^[49]^[50]

Strategies for osteoarthritis gene therapy

In the context of OA, the most attractive intra- articular sites for gene transfer are the synovium and the articular cartilage. Most experimental progress has been made with gene transfer to a convenient intra-articular tissue, such as the synovium, a tissue amenable to genetic modification by a variety of vectors, using both in vivo and ex vivo protocols.

Gene transfer to synovium

The major purpose of gene delivery is to alter the lining of the joint in a way that enables them to serve as an endogenous source of therapeutic molecules (Table-1) therapeutic molecules can diffuse and influence the metabolism of adjacent tissues such as cartilage. Genes may be delivered to synovium in animal models of RA and OA by direct, in vivo injection of vector or by indirect, ex vivo methods involving autologous synovial cells, skin fibroblasts, or other cell types such as mesenchymal stem cells.

The direct in vivo approach is intra-articular insertion of a vector to affect synovicytes. Vectors play crucial role in success of this method.^[51] The effect of Different vectors for in vivo gene delivery to synovium is summarized in Table 2:

**Table 2- Performance of different vectors for in vivo gene delivery to synovium** ^[41]
Vector	Comment
Adeno-associated virus	Excellent transduction efficiency and biocompatibility in joints
Adenovirus	Highly inflammatory with dose-dependent side-effects in joints
Retrovirus	No transduction of normal synovium; modest transduction of inflamed synovium
Lentivirus	High transduction of joint cells, but may cause oncogenic integrations
Herpes simplex virus	Highly efficient transduction; cytotoxic
Non-viral Vectors	Short-term and less efficient transfection; may promote inflammation

The indirect ex vivo approach involves harvest of synovium, isolation and culture of synoviocytes, in vitro transduction, and injection of engineered synovicytes into the joint.^[52]

Gene transfer to cartilage

Contrary to the synoviocytes which are dividing cells and can be transduced in vivo with high efficacy using either liposomes or viral vectors, in vivo delivery of genes to chondrocytes is hindered by the dense extra cellular matrix that surrounds these cells. Chondrocytes are non- dividing cells, embedded in a network of collagens and proteoglycans; however researches suggest that genes can be transferred to chondrocytes within normal cartilage by intraarticular injection of liposomes containing sendai virus (HVJ- liposomes) ^[53] and adeno-associated virus.^[54]^[55]

Most efficient methods of gene transfer to cartilage have involved ex vivo strategies using chondrocytes or chondroprogenitor cells. Chondrocytes are genetically enhanced by transferring complementary DNA encoding IL-1RA, IGF-1, or matrix break down inhibitors mentioned in Table 1. As discussed before, the transplanted cells could serve as an intra- articular source of therapeutic molecules.^[41]

Safety

One important issue related to human gene therapy is safety, particularly for the gene therapy of non-fatal diseases such as OA. The main concern is the high immunogenicity of certain viral vectors. Retroviral vectors integrate into the chromosomes of the cells they infect. There will be always a chance of integrating into a tumor suppressor gene or an oncogene, leading to virulent transformation of the cell.^[56]

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^ Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB (July 1992). "The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci". Genomics. 13 (3): 654–657. doi:10.1016/0888-7543(92)90137-H. PMID 1386337.
^ Arend WP, Evans CH (2003). "Interleukin-1 receptor antagonist [IL-1F3]". In Thomson AW, Lotze MT (eds.). The Cytokine Handbook. London: Academic Press. pp. 669–708. doi:10.1016/b978-012689663-3/50032-6. ISBN 978-0-12-689663-3.
^ Fernandes JC, Martel-Pelletier J, Caron JP, et al. (1996). "Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression". Arthritis Rheum. 39 (9): 1535–1544. doi:10.1002/art.1780390914. PMID 8814066.
^ Tardif G, Martel-Pelletier J, Fernandes J, et al. (1999). "In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression". American Journal of Pathology. 154 (4): 1159–1169. doi:10.1016/s0002-9440(10)65368-0. PMC 1866546. PMID 10233854.
^ Ghivizzani SC, Robbins PD, Frisbie DD, et al. (2002). "Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene". Gene Therapy. 9 (1): 12–20. doi:10.1038/sj.gt.3301608. PMID 11850718.
^ "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-07-23.
^ "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-07-23.
^ C. H.; Robbins, P. D. Evans (1994). Gene therapy for arthritis. pp. 320–343. doi:10.1007/978-1-4684-6822-9_18. ISBN 978-1-4684-6824-3. {{cite book}}: |journal= ignored (help)
^ Bandara, G.; et al. (1990). "Intraarticular expression of biologically active interleukin-1 receptor antagonist protein by ex vivo gene transfer". Proc. Natl. Acad. Sci. U.S.A. 90 (22): 10764–10768. Bibcode:1993PNAS...9010764B. doi:10.1073/pnas.90.22.10764. PMC 47858. PMID 8248169.
^ Hashimoto H, Tomita N, Tomita T, et al. (1997). "In vivo direct gene transfer into articular cartilage by intra-articular injection mediated by HVJ (sendai) virus and liposomes". Arthritis Rheum. 40 (5): 901–906. doi:10.1002/art.1780400518. PMID 9153552.
^ Schwartz E (2000). "The adeno-associated virus vector for orthopaedic gene therapy". Clinical Orthopaedics and Related Research. 379 (379 Suppl): 31–40. doi:10.1097/00003086-200010001-00005. PMID 11039749.
^ Yoo U, Mandell I, Angele P, et al. (2000). "Chondroprogenitor cells and gene therapy". Clin Orthop: 164–170.
^ Anderson WF, W. (1992). "Human gene therapy". Science. 256 (5058): 808–813. doi:10.1126/science.1589762. PMID 1589762.

[evans-1] Evans, C. H; Ghivizzani, S. C; Robbins, P. D (2018). "Gene Delivery to Joints by Intra-Articular Injection". Human Gene Therapy. 29 (1): 2–14. doi:10.1089/hum.2017.181. PMC 5773261. PMID 29160173.

[2] "Osteoarthritis (OA) | Arthritis | CDC". www.cdc.gov. 2020-08-04. Retrieved 2023-07-23.

[3] West, Christopher R.; Bedard, Nicholas A.; Duchman, Kyle R.; Westermann, Robert W.; Callaghan, John J. (2019). "Rates and Risk Factors for Revision Hip Arthroscopy". The Iowa Orthopaedic Journal. 39 (1): 95–99. ISSN 1555-1377. PMC 6604537. PMID 31413682.

[4] King, Lauren K.; March, Lyn; Anandacoomarasamy, Ananthila (2013). "Obesity & osteoarthritis". The Indian Journal of Medical Research. 138 (2): 185–193. ISSN 0975-9174. PMC 3788203. PMID 24056594.

[5] West, Christopher R.; Bedard, Nicholas A.; Duchman, Kyle R.; Westermann, Robert W.; Callaghan, John J. (2019). "Rates and Risk Factors for Revision Hip Arthroscopy". The Iowa Orthopaedic Journal. 39 (1): 95–99. ISSN 1555-1377. PMC 6604537. PMID 31413682.

[6] Aspden, R. M.; Saunders, F. R. (2019-01-30). "Osteoarthritis as an organ disease: from the cradle to the grave". European Cells & Materials. 37: 74–87. doi:10.22203/eCM.v037a06. ISSN 1473-2262. PMID 30698270.

[7] Shane Anderson, A.; Loeser, Richard F. (2010-02). "Why is osteoarthritis an age-related disease?". Best Practice & Research. Clinical Rheumatology. 24 (1): 15–26. doi:10.1016/j.berh.2009.08.006. ISSN 1532-1770. PMC 2818253. PMID 20129196. {{cite journal}}: Check date values in: |date= (help)

[8] Kampen, W. U.; Tillmann, B. (1998-12). "Age-related changes in the articular cartilage of human sacroiliac joint". Anatomy and Embryology. 198 (6): 505–513. doi:10.1007/s004290050200. ISSN 0340-2061. PMID 9833689. {{cite journal}}: Check date values in: |date= (help)

[9] Bobacz, K.; Erlacher, L.; Smolen, J.; Soleiman, A.; Graninger, W. B. (2004-12-01). "Chondrocyte number and proteoglycan synthesis in the aging and osteoarthritic human articular cartilage". Annals of the Rheumatic Diseases. 63 (12): 1618–1622. doi:10.1136/ard.2002.002162. ISSN 0003-4967. PMID 15547085.

[10] Kampen, W. U.; Tillmann, B. (1998-12). "Age-related changes in the articular cartilage of human sacroiliac joint". Anatomy and Embryology. 198 (6): 505–513. doi:10.1007/s004290050200. ISSN 0340-2061. PMID 9833689. {{cite journal}}: Check date values in: |date= (help)

[:0-11] ^ ^a ^b ^c ^d ^e ^f Hollander, Judith M.; Goraltchouk, Alex; Rawal, Miraj; Liu, Jingshu; Luppino, Francesco; Zeng, Li; Seregin, Alexey (2023-03-06). "Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism". Cartilage: 19476035231158774. doi:10.1177/19476035231158774. ISSN 1947-6043. PMID 36879540.

[12] Nixon, Alan J.; Grol, Matthew W.; Lang, Hayley M.; Ruan, Merry Z. C.; Stone, Adrianne; Begum, Laila; Chen, Yuqing; Dawson, Brian; Gannon, Francis; Plutizki, Stanislav; Lee, Brendan H. L.; Guse, Kilian (2018-11). "Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models". Arthritis & Rheumatology (Hoboken, N.J.). 70 (11): 1757–1768. doi:10.1002/art.40668. ISSN 2326-5205. PMID 30044894. {{cite journal}}: Check date values in: |date= (help)

[13] Evans, Christopher H.; Ghivizzani, Steven C.; Robbins, Paul D. (2023-01-01). "Osteoarthritis gene therapy in 2022". Current Opinion in Rheumatology. 35 (1): 37–43. doi:10.1097/BOR.0000000000000918. ISSN 1531-6963. PMC 9757842. PMID 36508307.

[14] Fujii, Yuta; Liu, Lin; Yagasaki, Lisa; Inotsume, Maiko; Chiba, Tomoki; Asahara, Hiroshi (2022-06-05). "Cartilage Homeostasis and Osteoarthritis". International Journal of Molecular Sciences. 23 (11): 6316. doi:10.3390/ijms23116316. ISSN 1422-0067. PMC 9181530. PMID 35682994.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[15] Seol, Dongrim; Choe, Hyeong Hun; Zheng, Hongjun; Brouillette, Marc J.; Fredericks, Douglas C.; Petersen, Emily B.; Song, Ino; Chakka, Leela R. J.; Salem, Aliasger K.; Martin, James A. (2022-05). "Intra-Articular Adeno-Associated Virus-Mediated Proteoglycan 4 Gene Therapy for Preventing Posttraumatic Osteoarthritis". Human Gene Therapy. 33 (9–10): 529–540. doi:10.1089/hum.2021.177. ISSN 1557-7422. PMC 9142765. PMID 34610749. {{cite journal}}: Check date values in: |date= (help)

[:1-16] ^ ^a ^b ^c ^d ^e ^f ^g ^h Eckstein, Felix; Hochberg, Marc C.; Guehring, Hans; Moreau, Flavie; Ona, Victor; Bihlet, Asger Reinstrup; Byrjalsen, Inger; Andersen, Jeppe Ragnar; Daelken, Benjamin; Guenther, Oliver; Ladel, Christoph; Michaelis, Martin; Conaghan, Philip G. (2021-08). "Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study". Annals of the Rheumatic Diseases. 80 (8): 1062–1069. doi:10.1136/annrheumdis-2020-219181. ISSN 1468-2060. PMC 8292562. PMID 33962962. {{cite journal}}: Check date values in: |date= (help)

[17] C. Wayne McIlwraith David D. Frisbie; McIlwraith, C. W. (Aug 2001). "Gene Therapy: Future Therapies in Osteoarthritis". Vet Clin North Am Equine Pract. 17 (2): 233–243. doi:10.1016/S0749-0739(17)30059-7. PMID 15658173.

[3_evans_gouz-18] CH Evans; JN Gouze; E Gouze; PD Robbins; SC Ghivizzani (2004). "Osteoarthritis gene therapy". Gene Therapy. 11 (4): 379–389. doi:10.1038/sj.gt.3302196. PMID 14724685. S2CID 25482399.

[8_sara-19] Madry, H.; Luyten, F.P.; Facchini, A. (2011). "Biological aspects of early osteoarthritis". Knee Surgery, Sports Traumatology, Arthroscopy. 20 (3): 407–422. doi:10.1007/s00167-011-1705-8. PMID 22009557. S2CID 31367901.

[10_sasa-20] Buckwalter, J.A.; Mankin, H.J. (1997). "Instructional Course Lectures, The American Academy of Ortopaedic Surgeons – Articular cartilage: Part II.Degeneration and osteoarthritis, repair, regeneration, and transplantation". J Bone Joint Surg Am. 4. 79 (14): 612–632. doi:10.2106/JBJS.J.01935. PMID 22810408.^{[clarification needed]}

[11_sasa-21] Felson, D.T., David T.; Lawrence, R.C.; Dieppe, P.A.; Hirsch, R.; et al. (2000). "Osteoarthritis: new insights. Part 1: the disease and its risk factors". Annals of Internal Medicine. 133 (8): 635–646. doi:10.7326/0003-4819-133-8-200010170-00016. PMID 11033593.

[22] "Osteoarthritis (OA) | Arthritis | CDC". www.cdc.gov. 2020-08-04. Retrieved 2023-07-23.

[23] Shane Anderson, A.; Loeser, Richard F. (2010-02). "Why is osteoarthritis an age-related disease?". Best Practice & Research. Clinical Rheumatology. 24 (1): 15–26. doi:10.1016/j.berh.2009.08.006. ISSN 1532-1770. PMC 2818253. PMID 20129196. {{cite journal}}: Check date values in: |date= (help)

[24] Gandhi, Rajiv; Wasserstein, David; Razak, Fahad; Davey, J. Roderick; Mahomed, Nizar N. (2010-12). "BMI independently predicts younger age at hip and knee replacement". Obesity (Silver Spring, Md.). 18 (12): 2362–2366. doi:10.1038/oby.2010.72. ISSN 1930-739X. PMID 20379147. {{cite journal}}: Check date values in: |date= (help)

[sarraf-25] Antonios G. Mikos A. Saraf (2006). "Gene delivery strategies for cartilage tissue engineering". Advanced Drug Delivery Reviews. 58 (4): 592–603. doi:10.1016/j.addr.2006.03.005. PMC 2702530. PMID 16766079.

[26] Ertl, Hildegund C. J. (2022). "Immunogenicity and toxicity of AAV gene therapy". Frontiers in Immunology. 13: 975803. doi:10.3389/fimmu.2022.975803. ISSN 1664-3224. PMC 9411526. PMID 36032092.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[27] Chen, Xin; Lim, Daniel A.; Lawlor, Michael W.; Dimmock, David; Vite, Charles H.; Lester, Thomas; Tavakkoli, Fatemeh; Sadhu, Chanchal; Prasad, Suyash; Gray, Steven J. (2023-02). "Biodistribution of Adeno-Associated Virus Gene Therapy Following Cerebrospinal Fluid-Directed Administration". Human Gene Therapy. 34 (3–4): 94–111. doi:10.1089/hum.2022.163. ISSN 1043-0342. {{cite journal}}: Check date values in: |date= (help)

[28] Evans, Christopher H.; Ghivizzani, Steven C.; Robbins, Paul D. (2018-01). "Gene Delivery to Joints by Intra-Articular Injection". Human Gene Therapy. 29 (1): 2–14. doi:10.1089/hum.2017.181. ISSN 1557-7422. PMC 5773261. PMID 29160173. {{cite journal}}: Check date values in: |date= (help)

[29] Aalbers, Caroline J.; Bevaart, Lisette; Loiler, Scott; de Cortie, Karin; Wright, J. Fraser; Mingozzi, Federico; Tak, Paul P.; Vervoordeldonk, Margriet J. (2015). "Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interferon-β (ART-I02) for Local Treatment of Patients with Rheumatoid Arthritis". PloS One. 10 (6): e0130612. doi:10.1371/journal.pone.0130612. ISSN 1932-6203. PMC 4479517. PMID 26107769.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[30] Payne, K. A.; Lee, H. H.; Haleem, A. M.; Martins, C.; Yuan, Z.; Qiao, C.; Xiao, X.; Chu, C. R. (2011-08-01). "Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees". Osteoarthritis and Cartilage. 19 (8): 1058–1065. doi:10.1016/j.joca.2011.04.009. ISSN 1063-4584.

[31] G. Kaul H. Madry; et al. (2005). "Trippel, Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)". Gene Therapy. 12 (15): 1171–1179. doi:10.1038/sj.gt.3302515. PMID 15815701.

[32] T.M. Maris; R. Gelberman; M. Boyer; M. Silva; D. Amiel R.S. Goomer (2000). "Nonviral in vivo Gene Therapy for tissue engineering of articular cartilage and tendon repair". Clin. Orthop. Relat. Res. 379 (379 Suppl): 189–200. doi:10.1097/00003086-200010001-00025. PMID 11039769. S2CID 26414603.

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[:2-37] Conaghan, P. G.; Katz, N.; Hunter, D.; Guermazi, A.; Hochberg, M.; Somberg, K.; Clive, J.; Johnson, M.; Goel, N. (2023-06-01). "Pos1348 Effects of Sprifermin on a Novel Outcome of Osteoarthritis Symptom Progression: Post-Hoc Analysis of the Forward Randomized Trial". Annals of the Rheumatic Diseases. 82 (Suppl 1): 1025–1026. doi:10.1136/annrheumdis-2023-eular.2454. ISSN 0003-4967.

[38] Haupt JL; et al. (2005). "Transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model". Journal of Orthopaedic Research. 23 (1): 118–126. doi:10.1016/j.orthres.2004.06.020. PMID 15607883.

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[40] Piercarlo Sarzi-Puttini; et al. (2005). "Osteoarthritis: An Overview of the Disease and Its Treatment Strategies". Seminars in Arthritis and Rheumatism. 35 (1): 1–10. doi:10.1016/j.semarthrit.2005.01.013. PMID 16084227.

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[42] Cole AA Kuettner KE, K; Cole, A (Feb 2005). "Cartilage degeneration in different human joints". Osteoarthritis and Cartilage. 13 (2): 93–103. doi:10.1016/j.joca.2004.11.006. PMID 15694570.

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[44] Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB (July 1992). "The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci". Genomics. 13 (3): 654–657. doi:10.1016/0888-7543(92)90137-H. PMID 1386337.

[45] Arend WP, Evans CH (2003). "Interleukin-1 receptor antagonist [IL-1F3]". In Thomson AW, Lotze MT (eds.). The Cytokine Handbook. London: Academic Press. pp. 669–708. doi:10.1016/b978-012689663-3/50032-6. ISBN 978-0-12-689663-3.

[46] Fernandes JC, Martel-Pelletier J, Caron JP, et al. (1996). "Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression". Arthritis Rheum. 39 (9): 1535–1544. doi:10.1002/art.1780390914. PMID 8814066.

[47] Tardif G, Martel-Pelletier J, Fernandes J, et al. (1999). "In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression". American Journal of Pathology. 154 (4): 1159–1169. doi:10.1016/s0002-9440(10)65368-0. PMC 1866546. PMID 10233854.

[48] Ghivizzani SC, Robbins PD, Frisbie DD, et al. (2002). "Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene". Gene Therapy. 9 (1): 12–20. doi:10.1038/sj.gt.3301608. PMID 11850718.

[49] "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-07-23.

[50] "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-07-23.

[51] C. H.; Robbins, P. D. Evans (1994). Gene therapy for arthritis. pp. 320–343. doi:10.1007/978-1-4684-6822-9_18. ISBN 978-1-4684-6824-3. {{cite book}}: |journal= ignored (help)

[52] Bandara, G.; et al. (1990). "Intraarticular expression of biologically active interleukin-1 receptor antagonist protein by ex vivo gene transfer". Proc. Natl. Acad. Sci. U.S.A. 90 (22): 10764–10768. Bibcode:1993PNAS...9010764B. doi:10.1073/pnas.90.22.10764. PMC 47858. PMID 8248169.

[53] Hashimoto H, Tomita N, Tomita T, et al. (1997). "In vivo direct gene transfer into articular cartilage by intra-articular injection mediated by HVJ (sendai) virus and liposomes". Arthritis Rheum. 40 (5): 901–906. doi:10.1002/art.1780400518. PMID 9153552.

[54] Schwartz E (2000). "The adeno-associated virus vector for orthopaedic gene therapy". Clinical Orthopaedics and Related Research. 379 (379 Suppl): 31–40. doi:10.1097/00003086-200010001-00005. PMID 11039749.

[55] Yoo U, Mandell I, Angele P, et al. (2000). "Chondroprogenitor cells and gene therapy". Clin Orthop: 164–170.

[56] Anderson WF, W. (1992). "Human gene therapy". Science. 256 (5058): 808–813. doi:10.1126/science.1589762. PMID 1589762.

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@@ Line 1: / Line 1: @@
 '''Gene therapy''' is being studied as a treatment for [[osteoarthritis]] (OA). Unlike pharmacological treatments which are administered [[Systemic administration|systemically]], [[gene therapy]] aims to establish sustained, synthesis of gene products and tissue rehabilitation within the joint.<ref name="evans">{{cite journal|last1=Evans|first1=C. H|last2=Ghivizzani|first2=S. C|last3=Robbins|first3=P. D|year=2018|title=Gene Delivery to Joints by Intra-Articular Injection|journal=Human Gene Therapy|volume=29|issue=1|pages=2–14|doi=10.1089/hum.2017.181|pmc=5773261|pmid=29160173}}</ref>
+The main risk factors for osteoarthritis are age<ref>{{Cite web |date=2020-08-04 |title=Osteoarthritis (OA) {{!}} Arthritis {{!}} CDC |url=https://www.cdc.gov/arthritis/basics/osteoarthritis.htm |access-date=2023-07-23 |website=www.cdc.gov |language=en-us}}</ref><ref>{{Cite journal |last=West |first=Christopher R. |last2=Bedard |first2=Nicholas A. |last3=Duchman |first3=Kyle R. |last4=Westermann |first4=Robert W. |last5=Callaghan |first5=John J. |date=2019 |title=Rates and Risk Factors for Revision Hip Arthroscopy |url=https://pubmed.ncbi.nlm.nih.gov/31413682/ |journal=The Iowa Orthopaedic Journal |volume=39 |issue=1 |pages=95–99 |issn=1555-1377 |pmc=6604537 |pmid=31413682}}</ref> and body mass index<ref>{{Cite journal |last=King |first=Lauren K. |last2=March |first2=Lyn |last3=Anandacoomarasamy |first3=Ananthila |date=2013 |title=Obesity & osteoarthritis |url=https://pubmed.ncbi.nlm.nih.gov/24056594/ |journal=The Indian Journal of Medical Research |volume=138 |issue=2 |pages=185–193 |issn=0975-9174 |pmc=3788203 |pmid=24056594}}</ref><ref>{{Cite journal |last=West |first=Christopher R. |last2=Bedard |first2=Nicholas A. |last3=Duchman |first3=Kyle R. |last4=Westermann |first4=Robert W. |last5=Callaghan |first5=John J. |date=2019 |title=Rates and Risk Factors for Revision Hip Arthroscopy |url=https://pubmed.ncbi.nlm.nih.gov/31413682/ |journal=The Iowa Orthopaedic Journal |volume=39 |issue=1 |pages=95–99 |issn=1555-1377 |pmc=6604537 |pmid=31413682}}</ref>, as such, OA is predominantly considered a disease of [[Ageing|aging]].<ref>{{Cite journal |last=Aspden |first=R. M. |last2=Saunders |first2=F. R. |date=2019-01-30 |title=Osteoarthritis as an organ disease: from the cradle to the grave |url=https://pubmed.ncbi.nlm.nih.gov/30698270/ |journal=European Cells & Materials |volume=37 |pages=74–87 |doi=10.22203/eCM.v037a06 |issn=1473-2262 |pmid=30698270}}</ref><ref>{{Cite journal |last=Shane Anderson |first=A. |last2=Loeser |first2=Richard F. |date=2010-02 |title=Why is osteoarthritis an age-related disease? |url=https://pubmed.ncbi.nlm.nih.gov/20129196/ |journal=Best Practice & Research. Clinical Rheumatology |volume=24 |issue=1 |pages=15–26 |doi=10.1016/j.berh.2009.08.006 |issn=1532-1770 |pmc=2818253 |pmid=20129196}}</ref> As the body ages, [[Catabolism|catabolic]] factors begin to predominate over [[Anabolism|anabolic]] factors resulting in a reduction in extracellular matrix gene expression<ref>{{Cite journal |last=Kampen |first=W. U. |last2=Tillmann |first2=B. |date=1998-12 |title=Age-related changes in the articular cartilage of human sacroiliac joint |url=https://pubmed.ncbi.nlm.nih.gov/9833689/ |journal=Anatomy and Embryology |volume=198 |issue=6 |pages=505–513 |doi=10.1007/s004290050200 |issn=0340-2061 |pmid=9833689}}</ref> and reduced cellularity<ref>{{Cite journal |last=Bobacz |first=K. |last2=Erlacher |first2=L. |last3=Smolen |first3=J. |last4=Soleiman |first4=A. |last5=Graninger |first5=W. B. |date=2004-12-01 |title=Chondrocyte number and proteoglycan synthesis in the aging and osteoarthritic human articular cartilage |url=https://ard.bmj.com/content/63/12/1618 |journal=Annals of the Rheumatic Diseases |language=en |volume=63 |issue=12 |pages=1618–1622 |doi=10.1136/ard.2002.002162 |issn=0003-4967 |pmid=15547085}}</ref><ref>{{Cite journal |last=Kampen |first=W. U. |last2=Tillmann |first2=B. |date=1998-12 |title=Age-related changes in the articular cartilage of human sacroiliac joint |url=https://pubmed.ncbi.nlm.nih.gov/9833689/ |journal=Anatomy and Embryology |volume=198 |issue=6 |pages=505–513 |doi=10.1007/s004290050200 |issn=0340-2061 |pmid=9833689}}</ref> in articular cartilage. As a result, catabolism eventually predominates over anabolism to such an extent that severe cartilage erosions and bone marrow lesions / remodeling manifest in clinical osteoarthritis. In addition, osteoarthritis has a number of heritable factors, and there may be genetic risk factors for the disease.
-Osteoarthritis has a high degree of heritable factors, and there may be genetic risk factors for the disease. Gene transfer strategies for the potential medical management of [[osteoarthritis]] are under preliminary research to define [[pathology|pathological]] mechanisms and possible treatments for this chronic disease. Both viral and non-viral vectors have been developed as a means to carry therapeutic genes and inject them into human cells.
+Gene augmentation<ref name=":0">{{Cite journal |last=Hollander |first=Judith M. |last2=Goraltchouk |first2=Alex |last3=Rawal |first3=Miraj |last4=Liu |first4=Jingshu |last5=Luppino |first5=Francesco |last6=Zeng |first6=Li |last7=Seregin |first7=Alexey |date=2023-03-06 |title=Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism |url=https://pubmed.ncbi.nlm.nih.gov/36879540/ |journal=Cartilage |pages=19476035231158774 |doi=10.1177/19476035231158774 |issn=1947-6043 |pmid=36879540}}</ref> and gene therapy<ref>{{Cite journal |last=Nixon |first=Alan J. |last2=Grol |first2=Matthew W. |last3=Lang |first3=Hayley M. |last4=Ruan |first4=Merry Z. C. |last5=Stone |first5=Adrianne |last6=Begum |first6=Laila |last7=Chen |first7=Yuqing |last8=Dawson |first8=Brian |last9=Gannon |first9=Francis |last10=Plutizki |first10=Stanislav |last11=Lee |first11=Brendan H. L. |last12=Guse |first12=Kilian |date=2018-11 |title=Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models |url=https://pubmed.ncbi.nlm.nih.gov/30044894/ |journal=Arthritis & Rheumatology (Hoboken, N.J.) |volume=70 |issue=11 |pages=1757–1768 |doi=10.1002/art.40668 |issn=2326-5205 |pmid=30044894}}</ref> strategies for the potential medical management of [[osteoarthritis]] are under preliminary research to define [[pathology|pathological]] mechanisms and possible treatments for this chronic disease. While viral-vector based gene therapies predominate, both viral and non-viral vectors have been developed as a means to carry therapeutic genes and inject them into human cells.<ref>{{Cite journal |last=Evans |first=Christopher H. |last2=Ghivizzani |first2=Steven C. |last3=Robbins |first3=Paul D. |date=2023-01-01 |title=Osteoarthritis gene therapy in 2022 |url=https://pubmed.ncbi.nlm.nih.gov/36508307/ |journal=Current Opinion in Rheumatology |volume=35 |issue=1 |pages=37–43 |doi=10.1097/BOR.0000000000000918 |issn=1531-6963 |pmc=9757842 |pmid=36508307}}</ref>
-== Theory ==
+== Theory of Gene Augmentation approaches ==
+As the body ages, catabolic factors begin to predominate over anabolic factors. In osteoarthritis, catabolic factors promote the degradation of articular cartilage and decrease the total cell content of cartilage.<ref>{{Cite journal |last=Fujii |first=Yuta |last2=Liu |first2=Lin |last3=Yagasaki |first3=Lisa |last4=Inotsume |first4=Maiko |last5=Chiba |first5=Tomoki |last6=Asahara |first6=Hiroshi |date=2022-06-05 |title=Cartilage Homeostasis and Osteoarthritis |url=https://pubmed.ncbi.nlm.nih.gov/35682994/ |journal=International Journal of Molecular Sciences |volume=23 |issue=11 |pages=6316 |doi=10.3390/ijms23116316 |issn=1422-0067 |pmc=9181530 |pmid=35682994}}</ref> While anabolic factors are able to replace the lost cartilage and cartilage producing cells when the organism is young, this ability is decreased with age. Gene Augmentation approaches, such as the delivery of [[FGF18]] and [[Proteoglycan 4|PRG4]] aim to augment the anabolic processes to delay the progression of cartilage degeneration.<ref name=":0" /><ref>{{Cite journal |last=Seol |first=Dongrim |last2=Choe |first2=Hyeong Hun |last3=Zheng |first3=Hongjun |last4=Brouillette |first4=Marc J. |last5=Fredericks |first5=Douglas C. |last6=Petersen |first6=Emily B. |last7=Song |first7=Ino |last8=Chakka |first8=Leela R. J. |last9=Salem |first9=Aliasger K. |last10=Martin |first10=James A. |date=2022-05 |title=Intra-Articular Adeno-Associated Virus-Mediated Proteoglycan 4 Gene Therapy for Preventing Posttraumatic Osteoarthritis |url=https://pubmed.ncbi.nlm.nih.gov/34610749/ |journal=Human Gene Therapy |volume=33 |issue=9-10 |pages=529–540 |doi=10.1089/hum.2021.177 |issn=1557-7422 |pmc=9142765 |pmid=34610749}}</ref> Catabolic factors appear to be successful in clinical studies when delivered in the form of repeat protein injections, however, due to the pharmacokinetics of articular joints, these approaches require up to 12 injections per year in bilateral osteoarthritis, and may need to be sustained indefinitely to prevent reversal of cartilage gains.<ref name=":1">{{Cite journal |last=Eckstein |first=Felix |last2=Hochberg |first2=Marc C. |last3=Guehring |first3=Hans |last4=Moreau |first4=Flavie |last5=Ona |first5=Victor |last6=Bihlet |first6=Asger Reinstrup |last7=Byrjalsen |first7=Inger |last8=Andersen |first8=Jeppe Ragnar |last9=Daelken |first9=Benjamin |last10=Guenther |first10=Oliver |last11=Ladel |first11=Christoph |last12=Michaelis |first12=Martin |last13=Conaghan |first13=Philip G. |date=2021-08 |title=Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study |url=https://pubmed.ncbi.nlm.nih.gov/33962962/ |journal=Annals of the Rheumatic Diseases |volume=80 |issue=8 |pages=1062–1069 |doi=10.1136/annrheumdis-2020-219181 |issn=1468-2060 |pmc=8292562 |pmid=33962962}}</ref> Gene Augmentation approaches aim to replicate the success of anabolic protein therapies by delivering the anabolic genetic instructions as a single injection treatment.<ref name=":0" />
+== Theory of Gene Replacement / Gene Therapy approaches ==
 Passing from parents to children, [[genes]] are the building blocks of inheritance. They contain instructions for making [[proteins]]. If genes do not produce the right proteins in a correct way, a child can have a genetic disorder. [[Gene therapy]] is a molecular method aiming to replace defective or absent genes, or to counteract the ones undergoing overexpression. For this purpose, three techniques may be utilized: gene isolation, manipulations, and transferring to target cells.<ref>{{cite journal|last1=C. Wayne McIlwraith David D. Frisbie|title=Gene Therapy: Future Therapies in Osteoarthritis|journal=Vet Clin North Am Equine Pract|date=Aug 2001|volume=17|issue=2|pages=233–243|pmid=15658173|last2=McIlwraith|first2=C. W.|doi=10.1016/S0749-0739(17)30059-7}}</ref> The most common form of gene therapy involves inserting a normal gene to replace an abnormal gene. Other approaches including repairing an abnormal gene and altering the degree to which a gene is turned on or off. Two basic methodologies are utilized to transfer vectors into target tissues; [[Ex vivo]] gene transfer and [[In-vivo]] gene transfer. One type of gene therapy in which the gene transfer takes place outside the patient's body is called ex vivo gene therapy. This method of gene therapy is more complicated but safer since it is possible to culture, test, and control the modified cells.
@@ Line 9: / Line 14: @@
 [[Osteoarthritis]] (OA) is a degenerative joint disease which is the western world's leading cause of pain and disability.<ref name="3 evans gouz">{{cite journal|author1=CH Evans |author2=JN Gouze |author3=E Gouze |author4=PD Robbins |author5=SC Ghivizzani |title=Osteoarthritis gene therapy|journal=Gene Therapy|year=2004|pages=379–389|doi=10.1038/sj.gt.3302196|pmid=14724685 |volume=11|issue=4 |s2cid=25482399 }}</ref><ref name="8 sara" >{{cite journal |author=Madry, H. |author2=Luyten, F.P. |author3=Facchini, A. |title=Biological aspects of early osteoarthritis|journal=Knee Surgery, Sports Traumatology, Arthroscopy|year=2011|doi=10.1007/s00167-011-1705-8|volume=20|issue=3|pages=407–422|pmid=22009557|s2cid=31367901 }}</ref> It is characterized by the progressive loss of normal structure and function of articular [[cartilage]], the smooth tissue covering the end of the moving bones.<ref name="10 sasa">{{cite journal |author=Buckwalter, J.A. |author2=Mankin, H.J. |title=Instructional Course Lectures, The American Academy of Ortopaedic Surgeons – Articular cartilage: Part II.Degeneration and osteoarthritis, repair, regeneration, and transplantation|journal=J Bone Joint Surg Am|year=1997|volume=79|issue=14|series=4|pages=612–632|doi=10.2106/JBJS.J.01935|pmid=22810408<!-- |first1=Esa|last2=Nevalainen|first2=Pasi|last3=Eskelinen|first3=Antti|last4=Huotari|first4=Kaisa|last5=Kalliovalkama|first5=Jarkko|last6=Moilanen|first6=Teemu -->}}{{clarify|reason=title does not agree with identifiers|date=April 2019}}</ref> This chronic disease not only affects the articular cartilage but the subchondral bone, the [[synovium]] and periarticular tissues are other candidates.<ref name="3 evans gouz" /> People with OA can experience severe pain and limited motion. OA is mostly the result of natural aging of the joint due to biochemical changes in the cartilage [[extracellular matrix]].<ref name="8 sara" /><ref name="11 sasa">{{cite journal| author=Felson, D.T. |author2=Lawrence, R.C. |author3=Dieppe, P.A. |author4=Hirsch, R. |title=Osteoarthritis: new insights. Part 1: the disease and its risk factors|journal=Annals of Internal Medicine|volume=133|issue=8|pages=635–646|doi=10.7326/0003-4819-133-8-200010170-00016|pmid=11033593|display-authors=etal |year=2000|first1=David T.|doi-access=free}}</ref>
-Osteoarthritis is caused by mechanical factors such as joint [[Trauma (medicine)|trauma]] and mechanical overloading of joints or joint-instability.<ref name=evans/><ref name="11 sasa" /> Since the degeneration of cartilage is an irreversible phenomenon, it is incurable, costly and responds poorly to treatment.<ref name="3 evans gouz" /> Due to the prevalence of this disease, the repair and regeneration of articular cartilage has become a dominant area of research.<ref name="10 sasa" /> The growing number of the people suffering from osteoarthritis and the effectiveness of the current treatments attract a great deal of attention to genetic-based therapeutic methods to treat the progression of this chronic disease.
+While age<ref>{{Cite web |date=2020-08-04 |title=Osteoarthritis (OA) {{!}} Arthritis {{!}} CDC |url=https://www.cdc.gov/arthritis/basics/osteoarthritis.htm |access-date=2023-07-23 |website=www.cdc.gov |language=en-us}}</ref><ref>{{Cite journal |last=Shane Anderson |first=A. |last2=Loeser |first2=Richard F. |date=2010-02 |title=Why is osteoarthritis an age-related disease? |url=https://pubmed.ncbi.nlm.nih.gov/20129196/ |journal=Best Practice & Research. Clinical Rheumatology |volume=24 |issue=1 |pages=15–26 |doi=10.1016/j.berh.2009.08.006 |issn=1532-1770 |pmc=2818253 |pmid=20129196}}</ref> and BMI<ref>{{Cite journal |last=Gandhi |first=Rajiv |last2=Wasserstein |first2=David |last3=Razak |first3=Fahad |last4=Davey |first4=J. Roderick |last5=Mahomed |first5=Nizar N. |date=2010-12 |title=BMI independently predicts younger age at hip and knee replacement |url=https://pubmed.ncbi.nlm.nih.gov/20379147/ |journal=Obesity (Silver Spring, Md.) |volume=18 |issue=12 |pages=2362–2366 |doi=10.1038/oby.2010.72 |issn=1930-739X |pmid=20379147}}</ref> are the main risk factors for Osteoarthritis, contributors such as joint [[Trauma (medicine)|trauma]] and mechanical overloading of joints or joint-instability can accelerate or exacerbate the condition.<ref name=evans/><ref name="11 sasa" /> Since the degeneration of cartilage is an irreversible phenomenon, it is incurable, costly and responds poorly to treatment.<ref name="3 evans gouz" /> Due to the prevalence of this disease, the repair and regeneration of articular cartilage has become a dominant area of research.<ref name="10 sasa" /> The growing number of the people suffering from osteoarthritis and the effectiveness of the current treatments attract a great deal of attention to genetic-based therapeutic methods to treat the progression of this chronic disease.
 == Vectors for osteoarthritis gene delivery ==
-Various [[vector (molecular biology)|vectors]] have been developed to carry the therapeutic genes to cells. There are two broad categories of gene delivery vectors: [[Viral vectors]], involving [[viruses]] and non-viral agents, such as [[polymers]] and [[liposomes]].<ref name=evans/><ref name="sarraf">{{cite journal|last=Antonios G. Mikos A. Saraf|title=Gene delivery strategies for cartilage tissue engineering|journal=Advanced Drug Delivery Reviews|year=2006|pages=592–603|doi=10.1016/j.addr.2006.03.005|pmid=16766079|volume=58|issue=4|pmc=2702530}}</ref>
+Various [[vector (molecular biology)|vectors]] have been developed to carry the therapeutic genes to cells. There are two broad categories of gene delivery vectors: [[Viral vectors]], involving [[viruses]] and non-viral agents, such as [[polymers]], [[lipid nanoparticles]], and [[liposomes]].<ref name=evans/><ref name="sarraf">{{cite journal|last=Antonios G. Mikos A. Saraf|title=Gene delivery strategies for cartilage tissue engineering|journal=Advanced Drug Delivery Reviews|year=2006|pages=592–603|doi=10.1016/j.addr.2006.03.005|pmid=16766079|volume=58|issue=4|pmc=2702530}}</ref>
 === Viral vectors ===
+[[Viral vectors]] are the most widely used gene delivery method as they have evolved to do this with a high degree of efficiency. When using viral vectors for gene delivery, researchers aim to remove all of the dangerous or pathogenic genes from the virus and replace them with at least one [[therapeutic]] gene. This makes the viral vectors highly effective at delivering the genetic cargo to cells, and significantly reduces the risks associated with using the viral vehicle.
-[[Viral vectors]] proved to be more successful in transfecting [[Cell (biology)|cells]] as their life cycles require them to transfer their own genes to the host cells with high efficiency. A virus infects the human by inserting its gene directly into their cells. This can be deadly, but the brilliant idea is to take advantage of this natural ability. The idea is to remove all the dangerous genes in the virus and inject the healthy human genes. So, viruses are inserting positive elements to the host cells while attacking them and they will be helpful rather than harmful.<ref name="4nk evans">{{cite journal|last1=Christopher H. Evans|title=Gene Therapies for Osteoarthritis|journal=Current Rheumatology Reports|year=2004|volume=6|issue=1|pages=31–40|doi=10.1007/s11926-004-0081-5|pmid=14713400|first1=Christopher H.|s2cid=43252961}}</ref>
+When administered systemically, or in high doses, viral vectors can induce an [[inflammation|inflammatory]] response, which can cause minor side effects such as [[edema]] or serious ones like multisystem organ failure.<ref>{{Cite journal |last=Ertl |first=Hildegund C. J. |date=2022 |title=Immunogenicity and toxicity of AAV gene therapy |url=https://pubmed.ncbi.nlm.nih.gov/36032092/ |journal=Frontiers in Immunology |volume=13 |pages=975803 |doi=10.3389/fimmu.2022.975803 |issn=1664-3224 |pmc=9411526 |pmid=36032092}}</ref> It may also be difficult to administer gene therapy repeatedly due to the immune system's enhanced response to viruses. However, viral vectors delivered locally to the joint, appear to be highly localized and well tolerated based on preclinical and early clinical studies.<ref>{{Cite journal |last=Chen |first=Xin |last2=Lim |first2=Daniel A. |last3=Lawlor |first3=Michael W. |last4=Dimmock |first4=David |last5=Vite |first5=Charles H. |last6=Lester |first6=Thomas |last7=Tavakkoli |first7=Fatemeh |last8=Sadhu |first8=Chanchal |last9=Prasad |first9=Suyash |last10=Gray |first10=Steven J. |date=2023-02 |title=Biodistribution of Adeno-Associated Virus Gene Therapy Following Cerebrospinal Fluid-Directed Administration |url=https://www.liebertpub.com/doi/10.1089/hum.2022.163 |journal=Human Gene Therapy |volume=34 |issue=3-4 |pages=94–111 |doi=10.1089/hum.2022.163 |issn=1043-0342}}</ref><ref>{{Cite journal |last=Evans |first=Christopher H. |last2=Ghivizzani |first2=Steven C. |last3=Robbins |first3=Paul D. |date=2018-01 |title=Gene Delivery to Joints by Intra-Articular Injection |url=https://pubmed.ncbi.nlm.nih.gov/29160173/ |journal=Human Gene Therapy |volume=29 |issue=1 |pages=2–14 |doi=10.1089/hum.2017.181 |issn=1557-7422 |pmc=5773261 |pmid=29160173}}</ref><ref>{{Cite journal |last=Aalbers |first=Caroline J. |last2=Bevaart |first2=Lisette |last3=Loiler |first3=Scott |last4=de Cortie |first4=Karin |last5=Wright |first5=J. Fraser |last6=Mingozzi |first6=Federico |last7=Tak |first7=Paul P. |last8=Vervoordeldonk |first8=Margriet J. |date=2015 |title=Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interferon-β (ART-I02) for Local Treatment of Patients with Rheumatoid Arthritis |url=https://pubmed.ncbi.nlm.nih.gov/26107769/ |journal=PloS One |volume=10 |issue=6 |pages=e0130612 |doi=10.1371/journal.pone.0130612 |issn=1932-6203 |pmc=4479517 |pmid=26107769}}</ref> Furthermore, the durability of therapeutic transgene expression appears to be such, that a single injection therapy may be sufficient to reverse progression of a disease.<ref>{{Cite journal |last=Payne |first=K. A. |last2=Lee |first2=H. H. |last3=Haleem |first3=A. M. |last4=Martins |first4=C. |last5=Yuan |first5=Z. |last6=Qiao |first6=C. |last7=Xiao |first7=X. |last8=Chu |first8=C. R. |date=2011-08-01 |title=Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees |url=https://www.sciencedirect.com/science/article/pii/S1063458411001269 |journal=Osteoarthritis and Cartilage |language=en |volume=19 |issue=8 |pages=1058–1065 |doi=10.1016/j.joca.2011.04.009 |issn=1063-4584}}</ref>
-While [[viral vectors]] are 40% more efficient in transferring genes, they are not fully appreciated for in vivo gene delivery because of their further adverse effects. Primarily, viral vectors induce an [[inflammation|inflammatory]] response, which can cause minor side effects such as mild [[edema]] or serious ones like multisystem organ failure. It is also difficult to administer gene therapy repeatedly due to the immune system's enhanced response to viruses. Furthermore, viruses may spread out to other organs after [[intraarticular]] injection and this will be an important disadvantage.<ref>{{cite journal|last1=N. Somia I.M. Verma|title=Gene Therapy — promises, problems and prospects|journal=Nature|volume=389|issue=6648|year=1997|pages=239–242|bibcode=1997Natur.389..239V|last2=Somia|first2=Nikunj|doi=10.1038/38410|pmid=9305836|first1=Inder M.|doi-access=free}}</ref> However, majority of problems associated with gene delivery using viral vectors solved by ex vivo gene delivery method. In Osteoarthritis gene therapy, ex vivo method makes it possible to transfect not only the cells of the synovial lining of joints but also articular [[chondrocytes]] and chondroprogenitor cells in cartilage.<ref>{{cite journal|last=Q.J. Jiang K. Gelse|title=Fibroblast-mediated delivery of growth factor complementary DNA into mouse joints induces chondrogenesis but avoids the disadvantages of direct viral gene transfer|journal=Arthritis Rheum|year=2001|pages=1943–1953|display-authors=etal |doi=10.1002/1529-0131(200108)44:8<1943::aid-art332>3.0.co;2-z|volume=44|issue=8|pmid=11508447|doi-access=free}}</ref>
 === Non-viral vectors ===
-Non-viral methods involve complexing therapeutic [[DNA]] to various [[macromolecules]] including cationic lipids and [[liposomes]], [[polymers]], [[polyamines]] and [[polyethylenimine]], and [[nanoparticles]].<ref name=evans/> FuGene 6 <ref>{{cite journal|last=G. Kaul H. Madry|title=Trippel, Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)|journal=Gene Therapy|year=2005|pages=1171–1179|display-authors=etal |doi=10.1038/sj.gt.3302515|pmid=15815701|volume=12|issue=15|doi-access=free}}</ref> and modified cationic liposomes <ref>{{cite journal|author1=T.M. Maris |author2=R. Gelberman |author3=M. Boyer |author4=M. Silva |author5=D. Amiel R.S. Goomer |title=Nonviral in vivo Gene Therapy for tissue engineering of articular cartilage and tendon repair|journal=Clin. Orthop. Relat. Res.|year=2000|pages=189–200|doi=10.1097/00003086-200010001-00025|volume=379|issue=379 Suppl |pmid=11039769 |s2cid=26414603 }}</ref> are two non-viral gene delivery methods that have so far been utilized for gene delivery to cartilage. FuGene 6 is a non-liposomal lipid formulation, which has proved to be successful in transfecting a variety of cell lines. Liposomes have shown to be an appropriate candidate for gene delivery,<ref>{{cite journal |vauthors=Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C|title=Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis|journal=Journal of Immunology|year=1998|volume=160|issue=11|pages=5213–5220|doi=10.4049/jimmunol.160.11.5213 |pmid=9605116|s2cid=6467223 }}</ref> where cationic liposomes are made to facilitate the interaction with the cell membranes and nucleic acids.<ref>{{cite journal|author1=J. Honiger |author2=D. Damotte |author3=A. Minty |author4=C. Fournier |author5=D. Fradelizi |author6=M. Boissier N. Bessis |title=Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA)|journal=Clinical & Experimental Immunology|year=1999|pages=376–382|doi=10.1046/j.1365-2249.1999.00959.x|pmid=10444273 |volume=117|issue=2 |pmc=1905333}}</ref>
+Non-viral methods involve complexing therapeutic [[DNA]] to various [[macromolecules]] including cationic lipids and [[liposomes]], [[polymers]], [[polyamines]] and [[polyethylenimine]], and [[nanoparticles]].<ref name=evans/> FuGene 6 <ref>{{cite journal|last=G. Kaul H. Madry|title=Trippel, Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)|journal=Gene Therapy|year=2005|pages=1171–1179|display-authors=etal |doi=10.1038/sj.gt.3302515|pmid=15815701|volume=12|issue=15|doi-access=free}}</ref> and modified cationic liposomes <ref>{{cite journal|author1=T.M. Maris |author2=R. Gelberman |author3=M. Boyer |author4=M. Silva |author5=D. Amiel R.S. Goomer |title=Nonviral in vivo Gene Therapy for tissue engineering of articular cartilage and tendon repair|journal=Clin. Orthop. Relat. Res.|year=2000|pages=189–200|doi=10.1097/00003086-200010001-00025|volume=379|issue=379 Suppl |pmid=11039769 |s2cid=26414603 }}</ref> are two non-viral gene delivery methods that have so far been utilized for gene delivery to cartilage. FuGene 6 is a non-liposomal lipid formulation, which has proved to be successful in transfecting a variety of cell lines. Liposomes have shown to be an appropriate candidate for gene delivery,<ref>{{cite journal |vauthors=Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C|title=Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis|journal=Journal of Immunology|year=1998|volume=160|issue=11|pages=5213–5220|doi=10.4049/jimmunol.160.11.5213 |pmid=9605116|s2cid=6467223 }}</ref> where cationic liposomes are made to facilitate the interaction with the cell membranes and nucleic acids.<ref>{{cite journal|author1=J. Honiger |author2=D. Damotte |author3=A. Minty |author4=C. Fournier |author5=D. Fradelizi |author6=M. Boissier N. Bessis |title=Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA)|journal=Clinical & Experimental Immunology|year=1999|pages=376–382|doi=10.1046/j.1365-2249.1999.00959.x|pmid=10444273 |volume=117|issue=2 |pmc=1905333}}</ref> Non-viral vectors may have the capacity to deliver a large amount of therapeutic genes repeatedly and may be lower cost to produce at large scale. Another advantage of non-viral delivery methods is that they do not elicit a memory immune response and may be administered several times. In spite of having advantages, non-viral vectors have not yet replaced viral vectors due to relatively low efficiency, toxicity, and short-term [[transgene]] expression.<ref name=sarraf /> As a result, while a number of viral vectors have successfully been used in several clinical studies, non-viral vectors for intra-articular delivery have thus far only been investigated preclinically.
-Unlike viral vectors, non-viral ones avoid the risk of acquiring replication competence. They have the capacity to deliver a large amount of therapeutic genes repeatedly, and it is convenient to produce them on a large scale. The most important of all, they do not elicit immune responses in the host organism. In spite of having advantages, non-viral vectors have not yet replaced viral vectors due to relatively low efficiency and short-term [[transgene]] expression.<ref name=sarraf />
-Novel non-viral vectors for osteoarthritis gene delivery including polymeric vectors are still under investigations.
 == Target cells in osteoarthritis gene therapy ==
+The cells targeted for the treatment of osteoarthritis are  [[chondrocytes]], [[synoviocytes]], and their [[Progenitor cell|progenitors]]. Since the joint capsule is relatively well contained, intra-articular injections are highly successful at delivering the therapeutic gene therapy locally to the target cell types.
-Target cells in the OA therapy are autologous [[chondrocytes]], Chondroprogenitor cells, Cells within the synovial cavity,<ref name=sarraf /> and cells of adjacent tissues such as [[muscle]], [[tendons]], [[ligaments]], and [[Meniscus (anatomy)|meniscus]].
-Development of cartilage function and structure may be achieved by:
+Treatment of osteoarthritis may be successful via:
+*Stimulation of [[anabolic]] pathways to rebuild the matrix or chondrocyte content - may result in reversal of the disease<ref name=":0" /><ref name=":1" /> (Examples include: FGF18).
-*Inhibiting inflammatory and [[catabolic]] pathways
+*Inhibition of [[catabolic]] pathways - may result in slowing of the disease progression, but not reversal (Examples include: IL-1Ra).
-*Stimulating [[anabolic]] pathways to rebuild the matrix
+*Replacing of the damaged cells or tissues - may result in reversal of the disease pathology<ref>{{Cite journal |last=Kon |first=Elizaveta |last2=Filardo |first2=Giuseppe |last3=Di Martino |first3=Alessandro |last4=Marcacci |first4=Maurilio |date=2012-03 |title=ACI and MACI |url=https://pubmed.ncbi.nlm.nih.gov/22624243/ |journal=The Journal of Knee Surgery |volume=25 |issue=1 |pages=17–22 |doi=10.1055/s-0031-1299651 |issn=1538-8506 |pmid=22624243}}</ref> (Examples include: MACI and Hyalofast).
-*Impeding cell [[senescence]]
+*Avoiding the pathological or symptomatic complications such as the reduction of pain or formation of [[osteophytes]]<ref>{{Cite journal |last=Hunter |first=David J. |date=2015-03-12 |title=Viscosupplementation for osteoarthritis of the knee |url=https://pubmed.ncbi.nlm.nih.gov/25760356/ |journal=The New England Journal of Medicine |volume=372 |issue=11 |pages=1040–1047 |doi=10.1056/NEJMct1215534 |issn=1533-4406 |pmid=25760356}}</ref> (Examples include, steroids and viscosupplements).
-*Avoiding the pathological formation of [[osteophytes]]
-*Prevention of [[apoptosis]], and/or influencing several of these processes <ref name="Hamburg">{{cite journal|author1=Magali Cucchiarini |author2=Henning Madry |title=Magali Cucchiarini and Henning Madry|journal=Experimental Orthopaedics and Osteoarthritis Research, Saarland University Medical Center|series=Homburg/Saar}}</ref>
+Thus far, the most promising therapies appear to be those focused on promoting cartilage anabolism. Specifically, only the chondro-anabolic [[FGF18]] therapy which uses the recombinant protein analog of FGF18, [[sprifermin]], has been able to demonstrate an ability to increase cartilage thickness in a dose-dependent manner<ref name=":1" />, arrest progression to joint replacement<ref name=":1" />, and reduce pain and clinically-meaningful symptom progression.<ref name=":1" /><ref name=":2">{{Cite journal |last=Conaghan |first=P. G. |last2=Katz |first2=N. |last3=Hunter |first3=D. |last4=Guermazi |first4=A. |last5=Hochberg |first5=M. |last6=Somberg |first6=K. |last7=Clive |first7=J. |last8=Johnson |first8=M. |last9=Goel |first9=N. |date=2023-06-01 |title=Pos1348 Effects of Sprifermin on a Novel Outcome of Osteoarthritis Symptom Progression: Post-Hoc Analysis of the Forward Randomized Trial |url=https://ard.bmj.com/content/82/Suppl_1/1025 |journal=Annals of the Rheumatic Diseases |language=en |volume=82 |issue=Suppl 1 |pages=1025–1026 |doi=10.1136/annrheumdis-2023-eular.2454 |issn=0003-4967}}</ref> Based on this success, FGF18 is also being investigated as a gene therapy for the treatment of OA.<ref name=":0" />
-Approaches influencing several of these processes simultaneously have also shown to be successful, like transferring the combination of inhibitors of catabolism pathways and activators of anabolic events ([[IGF-I]]/[[IL-1RA]]),<ref>{{cite journal|last=Haupt JL|title=Transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model|journal=Journal of Orthopaedic Research|year=2005|pages=118–126|display-authors=etal |doi=10.1016/j.orthres.2004.06.020|pmid=15607883|volume=23|issue=1|doi-access=free}}</ref> as well as that of activators of anabolic and proliferative processes (FGF- 2/SOX9 or FGF-2/IGF-I).<ref name=Hamburg />
+While several anti-inflammatory or anti-catabolic approaches have been reported in preclinical studies, none of the clinical studies to date have produced any evidence of efficacy. ([[IGF-I]]/[[IL-1RA]]),<ref>{{cite journal|last=Haupt JL|title=Transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model|journal=Journal of Orthopaedic Research|year=2005|pages=118–126|display-authors=etal |doi=10.1016/j.orthres.2004.06.020|pmid=15607883|volume=23|issue=1|doi-access=free}}</ref>.
 == Gene defects leading to osteoarthritis ==
-Osteoarthritis has a great degree of heritability.<ref>{{cite journal|last=MacGregor AJ|title=The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study|journal=Arthritis Rheum|year=2000|pages=2410–2416|doi=10.1002/1529-0131(200011)43:11<2410::aid-anr6>3.0.co;2-e|volume=43|issue=11|pmid=11083262|doi-access=free}}</ref> Forms of osteoarthritis caused by single gene mutation have better chance of treatment by gene therapy.<ref name="3 evans gouz" />
+While Osteoarthritis is mainly a disease of aging, it has some degree of heritability.<ref>{{cite journal|last=MacGregor AJ|title=The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study|journal=Arthritis Rheum|year=2000|pages=2410–2416|doi=10.1002/1529-0131(200011)43:11<2410::aid-anr6>3.0.co;2-e|volume=43|issue=11|pmid=11083262|doi-access=free}}</ref> Forms of osteoarthritis associated with genetic mutations may have an increased chance of treatment by gene therapy.<ref name="3 evans gouz" />
 [[Epidemiological]] studies have shown that a genetic component may be an important risk factor in OA.<ref>{{cite journal|last=Piercarlo Sarzi-Puttini|title=Osteoarthritis: An Overview of the Disease and Its Treatment Strategies|journal=Seminars in Arthritis and Rheumatism|year=2005|volume=35|issue=1|pages=1–10|display-authors=etal |pmid=16084227|doi=10.1016/j.semarthrit.2005.01.013}}</ref> [[Insulin-like growth factor I]] genes (IGF-1), [[Transforming growth factor]]β, [[cartilage oligomeric matrix protein]], [[bone morphogenetic protein]], and other anabolic gene candidates are among the candidate genes for OA.<ref name=sarraf /> Genetic changes in OA can lead to defects of a structural protein such as [[collagen]], or changes in the metabolism of bone and cartilage. OA is rarely considered as a simple disorder following [[Mendelian inheritance]] being predominantly a multifactorial disease.
-However, in the field of OA gene therapy, researches has more focused on gene transfer as a delivery system for therapeutic gene products, rather counteracting genetic abnormalities or [[genetic polymorphism|polymorphisms]]. Genes, which contribute to protect and restore the matrix of articular cartilage, are attracting the most attention. These Genes are listed in '''Table 1'''. Among all candidates listed below, proteins that block the actions of interleukin-1 (IL-1) or that promote the synthesis of cartilage matrix molecules have received the most experimental scrutiny.<ref name="4nk evans" />
+However, in the field of OA gene therapy, researches has focused on gene transfer as a delivery system for therapeutic gene products, rather counteracting genetic abnormalities or [[genetic polymorphism|polymorphisms]]. Genes, which contribute to protect and restore the matrix of articular cartilage, are attracting the most attention. These Genes are listed in '''Table 1'''. Among all candidates listed below, only FGF18 has been successful at a protein level in initial clinical studies.<ref name=":1" /> Other candidates, such as proteins that block the actions of interleukin-1 (IL-1) (interleukin-1 receptor antagonists / IL-1Ra) have been evaluated as both protein or gene therapy injections and were either abandoned (as in the case of the protein) or did not report any efficacy.
 {| border="1" cellpadding="2" align="center"
-|+ '''Table 1- Candidates for OA gene therapy''' <ref name="3 evans gouz" /><ref name="4nk evans" />
+|+ '''Table 1- Candidates for OA gene therapy''' <ref name="3 evans gouz" /><ref name="4nk evans">{{cite journal |last1=Christopher H. Evans |first1=Christopher H. |year=2004 |title=Gene Therapies for Osteoarthritis |journal=Current Rheumatology Reports |volume=6 |issue=1 |pages=31–40 |doi=10.1007/s11926-004-0081-5 |pmid=14713400 |s2cid=43252961}}</ref>
 |-
 ! style="background: #efefef;" | Category
-! colspan="2" style="background: #ffdead;" | Gene Candidate
+! style="background: #ffdead;" | Gene Candidate
+|-
+|Promotes cartilage formation
+|FGF18
 |-
 | Cytokine/cytokine antagonist || IL-1Ra, sIL-1R, sTNFR, IL-4
@@ Line 64: / Line 70: @@
 | Free radical antagonist || Super Oxide Dismutase
 |}
+== FGF18 as a target in osteoarthritis ==
+To date, the most promising preclinical evidence and clinical trial results have been derived from trials using [[FGF18]] protein or FGF18 gene therapy. Delivered as a protein, [[sprifermin]] (FGF18 analog), was able to increase cartilage thickness in a dose dependent manner in placebo controlled, randomized clinical studies.<ref name=":1" /> A result never previously achieved in osteoarthritis clinical history. The trial also demonstrated the potential of FGF18 to completely arrest progression to joint replacement over the study period. Finally, FGF18 was able to reduce pain (WOMAC) and clinically-meaningful symptom progression, in both the full trial population and the high-risk subgroup.<ref name=":1" /><ref name=":2" /> Based on these highly promising clinical results, FGF18 is being investigated as a gene therapy for the treatment of osteoarthritis.<ref name=":0" />
 == Interleukin-1 as a target in osteoarthritis ==
+While preclinical studies suggest that an anti-inflammatory [[Interleukin-1]] is a contributor to joint pain, cartilage loss, and inflammation, none of these findings have been confirmed in clinical studies.<ref>{{cite journal|last1=Cole AA Kuettner KE|title=Cartilage degeneration in different human joints|journal=Osteoarthritis and Cartilage|date=Feb 2005|volume=13|issue=2|pages=93–103|doi=10.1016/j.joca.2004.11.006|pmid=15694570|first1=K|last2=Cole|first2=A|doi-access=free}}</ref> A therapeutic gene with potential to counteract the effect of interleukin-1<ref>{{cite book|last=Dinarello CA|title=Interleukin-1 family;The Cytokine Handbook|year=2003|publisher=Academic Press|location=London}}</ref>, the [[Interleukin 1 receptor antagonist]] (IL-1Ra), is currently being evaluated in early clinical trials with several delivery vectors including AAV and adenovirus. The natural agonist of IL-1, is a protein that binds non-productively to the cell surface of interleukin-1 receptor, blocking the activity of IL-1 via the IL-1 receptor.<ref>{{cite journal|vauthors=Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB|title=The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci|journal=Genomics|date=July 1992|volume=13|issue=3|pages=654–657|doi=10.1016/0888-7543(92)90137-H|pmid=1386337}}</ref><ref>{{Cite book |vauthors=Arend WP, Evans CH |chapter=Interleukin-1 receptor antagonist [IL-1F3] |title=The Cytokine Handbook |veditors=Thomson AW, Lotze MT |location=London |publisher=Academic Press |year=2003 |pages=669–708 |doi=10.1016/b978-012689663-3/50032-6 |isbn=978-0-12-689663-3}}</ref>  A number of studies in dogs, rabbits, and horses suggested that local IL-1Ra gene therapy is safe and effective in animal models of OA<ref>{{cite journal|vauthors=Fernandes JC, Martel-Pelletier J, Caron JP |title=Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression|journal=Arthritis Rheum|year=1996|pages=1535–1544|display-authors=etal |doi=10.1002/art.1780390914|volume=39|issue=9|pmid=8814066|doi-access=free}}</ref><ref>{{cite journal|vauthors=Tardif G, Martel-Pelletier J, Fernandes J |title=In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression|journal=American Journal of Pathology|year=1999|pages=1159–1169|display-authors=etal |doi=10.1016/s0002-9440(10)65368-0|pmid=10233854|volume=154|issue=4|pmc=1866546}}</ref><ref>{{cite journal|vauthors=Ghivizzani SC, Robbins PD, Frisbie DD |title=Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene|journal=Gene Therapy|year=2002|pages=12–20|display-authors=etal |doi=10.1038/sj.gt.3301608|pmid=11850718|volume=9|issue=1|doi-access=free}}</ref>, however, none of these findings have translated to clinical efficacy despite both the protein and gene therapy being evaluated in multiple clinical trials.<ref>{{Cite web |title=CTG Labs - NCBI |url=https://clinicaltrials.gov/study/NCT00110916?cond=osteoarthritis&term=anakinra&rank=1 |access-date=2023-07-23 |website=clinicaltrials.gov}}</ref><ref>{{Cite web |title=CTG Labs - NCBI |url=https://clinicaltrials.gov/study/NCT02790723?cond=osteoarthritis&term=anakinra&rank=2 |access-date=2023-07-23 |website=clinicaltrials.gov}}</ref>
-Researches suggest that among all potential mediators, a protein called [[Interleukin-1]] is by far the most potent cause of the pain, joint inflammation and loss of cartilage associated with osteoarthritis.<ref>{{cite journal|last1=Cole AA Kuettner KE|title=Cartilage degeneration in different human joints|journal=Osteoarthritis and Cartilage|date=Feb 2005|volume=13|issue=2|pages=93–103|doi=10.1016/j.joca.2004.11.006|pmid=15694570|first1=K|last2=Cole|first2=A|doi-access=free}}</ref> A therapeutic gene used to treat the arthritic joins produces a second protein, which naturally counteracts the effect of interleukin-1.<ref>{{cite book|last=Dinarello CA|title=Interleukin-1 family;The Cytokine Handbook|year=2003|publisher=Academic Press|location=London}}</ref>
-The [[Interleukin 1 receptor antagonist]] (IL-1Ra), the natural agonist of IL-1, is a protein that binds non-productively to the cell surface of interleukin-1 receptor, therefore blocks the activities of IL-1 by preventing it from sending a signal to IL-1 receptor.<ref>{{cite journal|vauthors=Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB|title=The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci|journal=Genomics|date=July 1992|volume=13|issue=3|pages=654–657|doi=10.1016/0888-7543(92)90137-H|pmid=1386337}}</ref><ref>{{Cite book |vauthors=Arend WP, Evans CH |chapter=Interleukin-1 receptor antagonist [IL-1F3] |title=The Cytokine Handbook |veditors=Thomson AW, Lotze MT |location=London |publisher=Academic Press |year=2003 |pages=669–708 |doi=10.1016/b978-012689663-3/50032-6 |isbn=978-0-12-689663-3}}</ref>
-There are three main researches that prove the benefits of local IL-1Ra gene therapy in animal models of osteoarthritis [4]. Series of experiments on canines, rabbits, and horses demonstrate that local IL-1Ra gene therapy is safe and effective in animal models of OA, according to the fact that recombinant human IL-1Ra strongly protected the articular cartilage from degenerative changes.<ref>{{cite journal|vauthors=Fernandes JC, Martel-Pelletier J, Caron JP |title=Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression|journal=Arthritis Rheum|year=1996|pages=1535–1544|display-authors=etal |doi=10.1002/art.1780390914|volume=39|issue=9|pmid=8814066|doi-access=free}}</ref><ref>{{cite journal|vauthors=Tardif G, Martel-Pelletier J, Fernandes J |title=In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression|journal=American Journal of Pathology|year=1999|pages=1159–1169|display-authors=etal |doi=10.1016/s0002-9440(10)65368-0|pmid=10233854|volume=154|issue=4|pmc=1866546}}</ref><ref>{{cite journal|vauthors=Ghivizzani SC, Robbins PD, Frisbie DD |title=Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene|journal=Gene Therapy|year=2002|pages=12–20|display-authors=etal |doi=10.1038/sj.gt.3301608|pmid=11850718|volume=9|issue=1|doi-access=free}}</ref>
 == Strategies for osteoarthritis gene therapy ==
@@ Line 84: / Line 91: @@
 ! colspan="2" style="background: #ffdead;" | Comment
 |-
+| [[Adeno-associated virus]]|| Excellent transduction efficiency and biocompatibility in joints
-| Non-viral Vectors || Short-term and less efficient transfection; many inflammatory
+|-
+| [[Adenovirus]] || Highly inflammatory with dose-dependent side-effects in joints
 |-
 | [[Retrovirus]] || No transduction of normal synovium; modest transduction of inflamed synovium
 |-
-| [[Lentivirus]] || Extremely high transduction and transgene expression; no obvious side effects
+| [[Lentivirus]] || High transduction of joint cells, but may cause oncogenic integrations
-|-
-| [[Adenovirus]] || High transduction efficiency; dose-dependent inflammatory response
-|-
-| [[Adeno-associated virus]] || Moderate levels of transduction of normal and inflamed synovium
 |-
 | [[Herpes simplex virus]]|| Highly efficient transduction; cytotoxic
+|-
+| Non-viral Vectors || Short-term and less efficient transfection; may promote inflammation
 |-
 |}