Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches utilize three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout utilizes RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.
Oncolytic virotherapy is not a new idea – as early as the mid 1950s doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement; this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.
In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumours. In the 1940s–1950s some of the earliest human clinical trials with oncolytic viruses were started.
In 2015 the FDA approved the marketing of talimogene laherparepvec, a genetically engineered herpes virus, to treat melanoma lesions that cannot be operated on; it is injected directly into the lesion. As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis. Two genes were removed from the virus – one that shuts down an individual cell's defenses, and another that helps the virus evade the immune system – and a gene for human GM-CSF was added. The drug works by replicating in cancer cells, causing them to burst; it was also designed to stimulate an immune response but as of 2016, there was no evidence of this. The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011. It was the first oncolytic virus approved in the West.
Viral gene therapy
Viral gene therapy most frequently uses non-replicating viruses to deliver therapeutic genes to cells with genetic malfunctions. Early efforts while technically successful, faced considerable delays due to safety issues as the uncontrolled delivery of a gene into a host genome has the potential to disrupt tumour suppressing genes and induce cancer, and did so in two cases. Immune responses to viral therapies also pose a barrier to successful treatment, for this reason eye therapy for genetic blindness is attractive as the eye is an immune privileged site, preventing an immune response.
An alternative form of viral gene therapy is to deliver a gene which may be helpful in preventing disease that would not normally be expressed in the natural disease condition. For example, the growth of new blood vessels in cancer, known as angiogenesis, enables tumours to grow larger. However, a virus introducing anti-angiogenic factors to the tumour may be able to slow or halt growth.
Unlike traditional vaccines, in which attenuated or killed virus/bacteria is used to generate an immune response, viral immunotherapy uses genetically engineered viruses to present a specific antigen to the immune system. That antigen could be from any species of virus/bacteria or even human disease antigens, for example cancer antigens.
Vaccines are another method of virotherapy that use attenuated or inactivated viruses to develop immunity to disease. An attenuated virus is a weakened virus that incites a natural immune response in the host that is often undetectable. The host also develops potentially life-long immunity due to the attenuated virus’s similarity to the actual virus. Inactivated viruses are killed viruses that present a form of the antigen to the host. However, long-term immune response is limited.
There are two general approaches to develop these viruses using applied evolutionary techniques: Jennerian and Pastorian. The Jennerian method involves selecting similar viruses from non-human organisms to protect against a human virus while Pastorian methods use serial passage. This Pastorian method is very similar to directive evolution of oncolytic viruses. Selected viruses that target humans are passed through multiple non-human organisms for multiple generations. Over time the viruses adapt to the foreign environments of their new hosts. These now maladapted viruses have minimal capacity for harming humans and are used as attenuated viruses for clinical use. An important consideration is to not reduce the replicative ability of the virus beyond the point where the immune system response will be compromised. A secondary immune response would therefore be insufficient to provide protection against the live virus should it be reintroduced to the host.
Specific projects and products
RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004. It is wild type ECHO-7, a member of echovirus family. The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s. The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan. As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment. On March 19th, 2019, the manufacturer of ECHO-7, SIA LATIMA, announced the drug's removal from sale in Latvia, quoting financial and strategic reasons and insufficient profitability. However, several days later an investigative TV show revealed that State Agency of Medicines had run laboratory tests on the vials, and found that the amount of ECHO-7 virus is of a much smaller amount than claimed by the manufacturer. According to agency's lab director, "It's like buying what you think is lemon juice, but finding that what you have is lemon-flavored water". In March 2019, the distribution of ECHO-7 in Latvia has been stopped. 
Viral gene therapy
Viruses have been explored as a means to treat infections caused by protozoa. One such protozoa that potential virotherapy treatments have explored is Naegleria fowleri which causes primary amebic meningoencephalitis (PAM). With a mortality rate of 95%, this disease-causing eukaryote has one of the highest pathogenic fatalities known. Chemotherapeutic agents that target this amoeba for treating PAM have difficulty crossing blood-brain barriers. However, the driven evolution of virulent viruses of protozoal pathogens (VVPPs) may be able to develop viral therapies that can more easily access this eukaryotic disease by crossing the blood-brain barrier in a process analogous to bacteriophages. These VVPPs would also be self-replicating and therefore require infrequent administration with lower doses, thus potentially reducing toxicity.  While these treatment methods for protozoal disease may show great promise in a manner similar to bacteriophage viral therapy, a notable hazard is the evolutionary consequence of using viruses capable of eukaryotic pathogenicity. VVPPs will have evolved mechanisms of DNA insertion and replication that manipulate eukaryotic surface proteins and DNA editing proteins. VVPP engineering must therefore control for viruses that may be able to mutate and thereby bind to surface proteins and manipulate the DNA of the infected host.
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