Gene therapy

 Genes are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders develops. 

Gene therapy is a technique for correcting defective genes responsible for disease development. Several approaches can be used for correcting faulty genes:

·   A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.

·        An abnormal gene could be replaced with a normal gene through homologous recombination.

·        The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.

·        The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.

In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA.

Target cells such as the patient's liver or lung cells are infected with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state.

Gene therapy may be classified into two types:

Germ line gene therapy

Here germ cells, (sperm or eggs) are modified by the introduction of functional genes, which are integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations.

Somatic gene therapy

Here the therapeutic genes are transferred into the somatic cells of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited into later generations.

·       Some of the different types of viruses used as gene therapy vectors are Retroviruses (A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells), Adenoviruses (A class of viruses with double-stranded DNA genomes), Adeno-associated viruses (A class of single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome), Herpes simplex viruses (A class of double-stranded DNA viruses), etc.

·       Besides virus-mediated gene-delivery systems, there are several nonviral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA.

·       Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core (liposome). This liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell's membrane.

·       Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule that will bind to special cell receptors and get into the interior of the target cell.

·       Introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autonomously alongside the standard 46 --not affecting their workings or causing any mutations. A problem with this method is the difficulty in delivering such a large molecule to the nucleus of a target cell.

Gene Therapy in India

Gene Therapy can be a viable option for increasing the regeneration of the disease for which no other reliable treatment is available. The number of injections required for treating most of the conditions is comparatively low and costs less than the conventional alternatives, The advantages include long-term effects such as the possibility of permanent solutions for the conditions treated by gene therapy. The removal of problematic genes from the body of future parents also removes any chances of recurrence of the same condition in the next generation also.  Gene Therapy can treat Parkinson’s disease, muscular dystrophy, Kidney problems, eye diseases, neurodegenerative Diseases and Immune deficiencies.

Gene therapy in India is rapidly advancing, marked by the launch of affordable, indigenous CAR-T cell therapy for cancer (NexCAR19) from IIT Bombay in 2024.. The ICMR and DBT provide regulatory guidance, to make these costly therapies accessible and affordable for India's large patient population. The focus is on oncology, rare diseases, and genetic conditions like Muscular Dystrophy.

·        Cancer (CAR-T - Chimeric antigen receptor T cell Therapy):  India launched its first indigenous CAR-T cell therapy, NexCAR19, for B-cell malignancies, making advanced cancer treatment affordable.

T cells are the backbone of CAR T-cell therapy. Collect blood from the patient and separate out the T cells. These cells are then genetically engineered to produce special proteins on their surfaces called chimeric antigen receptors, or CARs. The CARs help the cells to bind on to specific antigens, that are present on cancer cells (and some normal cells). They enhance the T cells' ability to kill cancer cells. These modified T cells are grown, and returned to the patient as a single infusion. Currently, this entire process—from the initial blood collection to the cells being infused back into the patient—takes about 3 to 5 weeks. T cells will grow in the patient's body and, bind to cancer cells using their special receptors killing them.

·        Hemophilia A: A landmark trial showed successful gene therapy, eliminating the need for regular infusions by enabling patients to produce Factor VIII, offering a long-term solution.

·        Rare Diseases Focus: India is actively developing gene therapies for numerous rare genetic disorders, addressing a significant unmet need for conditions like Muscular Dystrophy, night blindness, and sickle cell anemia.

Disadvantages:

• Short-lived nature of gene therapy - The therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits.
• Immune response - Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system that reduces gene therapy effectiveness is always a potential risk.
• Problems with viral vectors – Viruses may cause toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
• Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be difficult to treat effectively using gene therapy.