Gene therapy is one of the most exciting areas of biotechnology, with respect to the current signs of progress as well as future possibilities. The advancements in technology, which have allowed the alteration of the immune system, control of nucleic acid delivery, and defined the manipulation of the human genome, have inspired whole new areas of medical research. The recent developments in gene therapy have paved a path for next-generation technologies. This article focuses on the future of gene therapy.
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Scientists are currently investigating gene therapies extensively to develop an effective methodology and minimize the risks and side effects of treatment. They opine that the past five years have brought about a renaissance in the field of gene and cell therapy. During this time, many therapies have been approved by global regulatory bodies. This includes the introduction of the first oligonucleotide-based therapies and two in vivo gene therapies, with many more in the pipeline. These therapies could cure multiple diseases, such as neuromuscular disease, inherited blindness, and cancer. Scientists and clinicians emphasized that these therapies have been life-changing for many affected patients.
An Overview of the Present and Future of Gene Therapy
As the name suggests, gene therapy involves modifying or manipulating gene expression to treat or cure diseases. Human genes contain DNA that controls every form and function of the body. A faulty gene causes disease, and this condition can be altered via gene therapy by replacing a faulty gene with a new gene to cure the disease or enhance the ability to fight against it. Scientists have suggested that gene therapy has the potential to treat a broad spectrum of diseases, such as cystic fibrosis, cancer, heart disease, hemophilia, diabetes, and AIDS.
Several mechanisms are involved in gene therapy, for example, replacing a disease-causing gene or mutated gene with a copy of a healthy gene. It also involves introducing a new or modified gene into the body that could cure diseases. Additionally, this technique is also associated with inactivating a faulty gene that is not functioning appropriately or fixing a mutated gene so that it can function normally.
Scientists have determined the potential risks associated with gene therapies and are working to alleviate them. For instance, a new gene cannot be directly inserted into a cell, instead, it has to be delivered via a carrier called a vector. Researchers have engineered various vectors to carry therapeutic genes into human cells, such as plasmid DNA, viral vector, and bacterial vectors. Additionally, the development of new technologies has aided gene therapies. These new technologies include human gene-editing technology and patient-derived cellular gene therapy, i.e., removing cells from patients, genetically modifying them, and replacing them in the body.
Some of the common risks associated with gene therapies include unwanted immune system reactions, especially while using bacterial or viral vectors, where the body’s immune system recognizes it as an intruder and attacks it. This may cause severe inflammation or even organ failure. Adverse effects could also occur if a viral vector carrying a mutated gene targets the wrong cells. Additionally, when these viruses are introduced into a body, they can sometimes regain their ability to cause infection.
Gene Therapy Basics
Future of Gene Therapy
One of the approved gene therapies is in vivo AAV gene transfer to the human retina and central nervous system for Leber’s congenital amaurosis (retinal dystrophy) and spinal muscular atrophy, respectively. This therapy has laid a foundation for developing AAV-based therapies for liver issues, hemophilia, skeletal muscle dystrophy, and Duchenne muscular dystrophy.
Additionally, the development of technology, such as ex vivo lentiviral and retroviral gene transfer to T cells, has paved the way for adoptive cell immunotherapy and therapies for inherited disorders (e.g., sickle cell disease and beta-thalassemia). Gene therapy for beta-thalassemia has been recently approved in the European Union and is under review in the US.
Although AAV-based gene therapies have proved to be highly successful, 50% of patients have to be excluded from this therapy owing to pre-existing immunity to the viral capsids. Therefore, scientists are currently working on next-generation technologies for the treatment of many human diseases while minimizing the risk of inducing immune responses.
Researchers believe that advancements in the engineering and profiling of non-viral nanoparticles for gene delivery and the recent approval of siRNA-based drugs would have a tremendous impact on future gene therapies. One of the key advantages of using nanoparticles in gene delivery is that they can evade the body’s immune responses.
The first-generation technologies, such as gene-editing technologies, have laid the foundation for an entirely new treatment modality based on a precise modification of human genome sequences. The success of CRISPR-based gene editing for sickle cell disease and beta-thalassemia has demonstrated that these technologies could also be applied for other diseases. Previous results have made scientists optimistic about the ongoing clinical trials of in vivo genome editings, such as AAV-based gene editing in the retina (EDIT-101) and a planned trial for non-viral nanoparticle-based delivery of CRISPR to the liver (NTLA-2001).
In the future, some of the high-cost therapies for targeted disorders need to be replaced with affordable therapies. The rate of technological innovation of genes has significantly outpaced the ability to assess the safety profiles of the treatment. According to current regulatory models, a large number of patients are required to establish the safety and efficacy of treatment. In the future, new genetic therapies will be developed for both common as well as rare diseases. Researchers stated that similar to biologics, gene therapies are also expected to see significant advances in the coming years.
Sources:
- Jensen, L.T. et al. (2021). Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord. Frontiers of Molecular Neuroscience. 14. DOI=10.3389/fnmol.2021.695937
- Dorholt, M. (2021) We’re on the Verge of a Breakthrough for Gene Therapies. [Online] Available at: https://www.evernorth.com/articles/the-history-and-future-of-gene-therapy
- Daley, J. (2021) Four Success Stories in Gene Therapy. [Online] Available at: https://www.scientificamerican.com/article/four-success-stories-in-gene-therapy/
- Bulaklak, K., and Gersbach, C.A. (2020). The once and future gene therapy. Nature Communications. 11, 5820. https://doi.org/10.1038/s41467-020-19505-2
- What is Gene Therapy? (2018) [Online] Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy
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