Gene Therapy: An Overview
MediopinionsThroughout history, humans have always wanted to find cures for the diseases ailing them. The general approach for this has always been diagnosis, followed by administering medicines or invasive surgical procedures to treat them and finally, post op care. But during the 20th century, the structure of DNA was found and it was confirmed as the genetic material in living organisms. Following this, the Human Genome Project was undertaken and over 3 billion human genes were sequenced. This completely transformed the way healthcare experts looked at human diseases. Then came Gene Therapy- which used components of a human’s own body to cure diseases, rather than using medicines synthesized in the labs to combat them. Gene therapy has shown to substantially improve the condition of a patient suffering from the disease, sometimes by completely curing them. Usually, when a medicine is administered to a patient, those bio-molecules are metabolized and circulated through the blood. As these molecules cannot be targeted to a particular site, they have a broad area of coverage, causing adverse side effects. Gene Therapy, on the other hand, targets a particular site and as a result, the side effects are minimal. Genes are composed of DNA which hold instructions to produce the necessary proteins required for the cells. When a disease occurs, it is due to the absence, malfunction or mutation of a gene. Due to this, the cells produce too much, too little or no protein. Gene therapy replaces the faulty genes with new genes or modified ones to ensure proper functioning. History of gene therapy Courtesy: https://www.thegenehome.com/what-is-gene-therapy/history Gene therapy has witnessed monumental evolution over the years. Some key milestones that has shaped gene therapy today: ● 1953 - Structure of DNA characterized by a double helix3 James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin King’s College London ● 1961-1966 - Genetic code discovered by deciphering the three bases of DNA in 1 of the 20 amino acids. The 19 remaining amino acids were deciphered soon after. Marshall Nirenberg, Har Khorana, and Severo Ochoa National Institutes of Health (NIH) ● 1973 - Genetic engineering technique allowing genetic material from an organism to be introduced, replicated, and expressed artificially into another. Stanley N. Cohen and Herbert W. Boyer US-Japan joint meeting on plasmids, Hawaii ● 1980 - Gene therapy tested in people without permission from the university who provided funding for the National Institutes of Health (NIH). The researcher lost multiple grants and NIH warned others that human experimentation would not be tolerated. Martin Cline The University of California, Los Angeles ● 1990 - First gene therapy clinical trial using new viral vector technology Michael Blaese and French Anderson National Institutes of Health (NIH) ● 1996 - First engineered nuclease technology for exploring the use of zinc finger nucleases for gene editing Yang-Gyum Kim, Jooyuen Cha, and Srinivasan Chandrasegaran Johns Hopkins University ● The first generation of lentiviral vectors (LVVs) created using three different plasmids containing a large deactivated portion of the HIV genome, making it unlikely for HIV to replicate in human cells ● Second and third generation LVVs followed a couple years later containing further reduction of the original HIV genome (less than two-thirds) Didier Trono and Luigi Naldini Salk Institute ● 1999 - The FDA and NIH created new programs—the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia—to ensure safe and transparent gene therapy clinical trials. University of Pennsylvania, Food and Drug Administration (FDA), National Institutes of Health (NIH) ● 2000 - Clinical trial of gene therapy using a gamma retrovirus raised concern about the safety of gene insertion Alain Fisher and Marina Cavazzana-Calvo Necker Hospital for Sick Children ● 2002 - First clinical trial using an LVV approved by the FDA - to test the safety and tolerability of a single infusion in patients with HIV. Rob Roy MacGregor University of Pennsylvania ● 2003 - The National Medical Products Administration, formerly the China Food and Drug Administration, approved the world’s first commercially available gene therapy to treat squamous cell carcinoma, a form of skin cancer. National Medical Products Administration China ● 2010 - The first engineered TAL-effector nucleases were described with the ability to cause targeted mutagenesis. Michelle Christian, Tomas Cermak, and Erin L. Doyle University of Minnesota and Iowa State University ● A self-inactivating LVV used in clinical trials of gene addition therapy in hemoglobinopathies Philippe Leboulch Paris Descartes University ● 2012 - The European Medicines Agency (EMA) approved the first AAV-based gene addition therapy for the treatment of lipoprotein lipase deficiency (LPLD) European Medicines Agency (EMA) Europe ● 2012 - Scientists developed a gene-editing technique called CRISPR/Cas9 that can modify specific DNA sequences Jennifer Doudna, Emmanuelle Charpentier, and team UC Berkeley ● 2016 - The EMA approved the first gamma retrovirus-based gene addition therapy to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). This therapy contains CD34+ cells transduced with retroviral vector, which encodes for the human ADA cDNA sequence European Medicines Agency (EMA) Europe ● 2017 - The FDA approved the first in vivo gene addition therapy to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy ● The FDA approved a CAR T-cell therapy for the treatment of patients with relapsed/refractory large B cell lymphoma (R/R DLBCL) Approved by the EMA in 201926 US Food and Drug Administration (FDA) United States ● 2018 - The first clinical trial using CRISPR/Cas9 was initiated. This study is investigating the use of CRISPR/Cas9 for gene disruption in beta hemoglobinopathies Stanford University, Columbia University, The Children’s Hospital at TriStar Centennial Medical Center ● 2019 - The FDA approved an AAV-based in vivo gene addition therapy for spinal muscular atrophy Conditionally approved by the EMA in 202029 US Food and Drug Administration (FDA) United States ● 2020 - FDA finalizes 6 gene therapy guidelines including draft guidelines for the research and clinical development of gene therapies US Food and Drug Administration (FDA) United States ● 2021 - A 4-day-old newborn received in vivo gene therapy for spinal muscular atrophy, making her the youngest patient at this point to receive gene therapy Charlotte Hollman Woman’s Hospital, Baton Rouge, LA, USA There are many methods in which Gene Therapy is done. Some of them are: 1. Gene Augmentation: A healthy gene is used in the place of a defective one. 2. Gene Inhibition: The gene responsible for producing harmful protein is deactivated. Another method which is used extensively is the viral vector method. For targeted transfer of genes, a delivery mechanism is required to transfer the genes to their respective locations. This is where the virus is used. Here, all the infectious and harmful parts of the virus are removed and the genetic material is transferred into it. The virus, being good at entering the cell, transfers the genetic material into the required location. Gene therapy is classified into 2 types: 1. In vivo therapy- This kind of gene therapy uses a vector to directly transfer the gene into the cell. Also, this is used in those cases where any one gene in the body is defective. 2. Ex vivo therapy- In this kind of therapy, the cells are extracted from the body, modified in the laboratory and sent back to the body. This is used for diseases like Leukaemia and Lymphoma. In Ex vivo therapy, the whole process of gene therapy, right from the creation of a gene to placing it inside the cell is monitored whereas in In Vivo therapy, the gene is simply transferred into the cell, which might increase the chances for an infection. Also, the In Vivo method is less expensive and less complicated than the Ex Vivo method. It also targets internal organs, in places where it is difficult to reach. Ex Vivo, on the other hand, is sometimes an invasive procedure, requiring more skills and effort. Moreover, be it In Vivo or Ex Vivo gene therapy, it offers a permanent solution to the disease and it is a single time procedure unlike surgeries which take multiple attempts to achieve its end result. Even though it’s only been a few years since the discovery of gene therapy, healthcare experts are positive about the immense potential it possesses to transform the way diseases are treated. Though only the trials are underway, even rare diseases like Sickle Cell Anemia and Hemophilia might be treatable in the future. Gene Therapy is indeed a boon to all of us, but we must also keep in mind the ethical concerns and unpredictable dangers that are associated with this new kind of treatment. In the future, healthcare experts must keep all such concerns in mind while carrying out treatments in this field.