According to Drugwatch®, a non-profit drug information network and organization, an estimated four million patients in the USA alone visit doctors annually due to adverse effects of prescription drugs. Hence, gene therapy that aligns with the natural human genetic transcriptome has the potential to become an unquestionable choice for complete treatment of diseases, disorders, and infectious diseases.
Gene therapy appears simple in principle but involves identification of affected gene(s), cloning and loading of a wild type or recombinant healthy version in a suitable vector for optimal delivery and expression in the target cells or tissue and thus, has seen its fair share of hurdles.
The European Medicines Agency (EMA) describes gene therapy medicinal product (GTMP) as a “biological medicinal product that contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to humans to regulate, repair, replace, add or delete genetic sequences and its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.” So, basically, gene therapy allows the delivery of therapeutic genetic material to any specific cell or tissue and/or organs of the body for treatment.
Based on the type of cells or tissues targeted for gene delivery and treatment, gene therapy is divided into germ-line and somatic cell gene therapies. Germ-line gene therapy involves genetic manipulation of the reproductive cells sperm and egg to make heritable changes. In somatic cell gene therapy, every cell except sperm and egg is targeted for therapeutic treatment. It is considered safe because genetic changes remain in the patient and are not passed onto the offspring.
Many advanced methods are being developed to deliver therapeutic genetic materials, and they are broadly divided into ex vivo, in situ, and in vivo methods. Ex vivo, also called “outside the living body” method, involves isolating the cells to be treated from the patient, modifying them with a therapeutic gene, and re-introducing into the patient’s body. In situ delivery, or “in position” delivery, involves administration of the desired genetic material directly into the target cells or tissue. The last and most important method of gene delivery is in vivo, or “in the living body.” In this method, viral, or non-viral vectors are used to deliver the therapeutic material to the defective target cells or tissue in the body.
There are a wide variety of physical and chemical delivery methods including needles, gene guns, electroporation, sonoporation, photoporation, magnetofection, and gold nanoparticles which are being used to deliver genetic material to target cells. However, none of them is more efficient than viruses in delivering therapeutic genetic materials to the target cells due to their inherent shortcomings and operational complexity.
Though the word virus implies mortality and morbidity, viruses are considered nature’s genetic engineers because of their ability to infect most kinds of organisms including bacteria, humans, animals, and plants. Also, viruses help certain plants to survive in extreme weather conditions.
Because of their abundance on the earth and difference in genetic makeup, many viruses are being used in preclinical and clinical investigations but each comes with its own unique advantages and disadvantages. Therefore, finding a suitable vector to deliver therapeutic genetic material has become a challenge to make gene therapy a viable and better treatment option than conventional methods.
An ideal vector has many characteristics, such as enough space to transport large therapeutic genes, high transduction efficiency, and the ability to provide long-term and stable expression, as well as target specific cells, avoid random insertion of the therapeutic gene into the host genome. It should not be immunogenic or pathogenic, should not cause inflammation and should possess the ability to be manufactured on a large scale.
Viruses display specificity in infecting cell types; therefore, viral vectors can be selected based on the type of cell that needs gene delivery. Some of the popular viruses currently in use include Adenovirus (AV) (made from the human adenoid tissue-derived cell cultures for the first time in 1953); adeno-associated virus (AAV); herpes simplex viruses (HSV); and Retroviruses (RV) which include several immunodeficiency viruses like human immunodeficiency virus (HIV), bovine immunodeficiency virus (BIV) feline immunodeficiency virus and mouse mammary tumor virus.
With encouraging clinical outcome being observed in a large number of ongoing clinical trials, especially in treating cancer, AV-mediated gene therapy is anticipated to make a significant impact on eradicating cancer in the near future.
Although the AV-mediated gene therapy carries a unique advantage over other systems, several concerns must be addressed to offer treatment without side effects. Development of AV particles that resist inactivation by serum proteins is necessary to promote intravenous administration of therapeutic particles during treatment. Development of strategies to avoid dose-associated toxicity is needed. In addition, contamination with replication-competent virus still remains a serious issue in large scale production of AV preparation for therapeutic purposes. Therefore, further advancement in the production of purified AV and AV-based gene delivery technologies is required for using gene therapy to its full potential. Like the concerns of the AV-mediated therapies, each of the other viral delivery systems (AAV, RV and HSV) has their own concerns and issues to be resolved.
Barriers to the use and acceptance of viral gene therapy are manifold. Since immunity is the primary barrier for the success of viral gene therapy, it is critical to design viral vectors that can subvert the complement system. An immune response could make a viral treatment less efficient, or the resulting creation of antibodies could preclude a second dosage of the same virus.
Additionally, a social stigma is associated with viral therapy. Most patients would be concerned about being infected by a live virus—a concern also held about viral vaccines. Since their ubiquitous presence is a reality, why shouldn’t humankind start accepting them as wonderful molecular biological tools with which to build novel and powerful medicine?
The world’s first gene therapy clinical study was conducted in 1989, and now 3704 gene therapy studies from 204 countries are listed in the US Government’s clinical trials database. More than 50% of them are being conducted in the USA alone. The US government recently has removed NIH special oversight rules on gene therapy studies, and the USFDA has decided to consider gene therapy drugs like other medications for approval in order to make gene therapy a therapeutic reality for patients.
Despite many technological challenges and barriers, more than a dozen gene therapy-based drugs have entered the world pharmaceutical market to date. Gene therapy drugs currently available in the market are specific to particular conditions or diseases and can come with a very hefty price tag.
The first ever approved gene therapy drug was approved in China for use in squamous cell head and neck carcinoma in 2003. According to the manufacturer, a single dose of Gendicine™, costing less than US $400, is given to patients once a week for 8 weeks as a cure. Gendicine™ has been given to more than 30,000 cancer patients, and it has displayed an exemplary safety record with no significant side effects to date. Unfortunately, no information is available about the submission of Gendicine™ clinical data for approval from the USFDA to date, and the USFDA has not approved a drug (Introgen’s Advexin) based on the same p53 gene because of concerns with the AV vector delivery after the death of a trial participant in 1999.
Recently, another retrovirus-based drug, Strimvelis™, was approved in Europe to treat an ultra-rare immunodeficiency syndrome, ADA-SCID, or Bubble Boy Syndrome, a fatal and life-threatening disease due to lymphopenia, and recurrent and opportunistic infections. The ADA gene is treated ex-vivo with Stimvelis and then reintroduced into the patients whose bodies can express protein to repair their immune system on their own. This drug, with a list price of $714,000, is available for ADA-SCID patients without a donor that has matched human leukocyte antigen (HLA). Amazingly, clinical studies revealed a 100% remission rate for Strimvelis™.
The USFDA has approved an HSV-based drug called T-VEC (Imlygic™) for melanoma treatment. T-VEC directly kills metastatic melanoma cells and enhances the immune response against them. The T-VEC treatment course involves a series of HSV injections into the melanoma lesions for 6 months for a complete cure.
Gene therapy is a rapidly expanding field, and it seems that scientists have only scratched the surface of its potential. The more that is discovered about how to optimize gene delivery vectors, the closer this field gets to delivering wide-scale solutions to modern medicine.
Undoubtedly, the interest in offering gene therapy-based treatments is one of the most defining developments in the pharmaceutical industry and is expected to have far-reaching implications on curing dangerous diseases in the future. With an estimated US $11 billion market in the next 10 years, both clinical trials and the pharmaceutical industry are anticipated to benefit immensely from gene therapy.