Going Beyond Gene Therapy 101: Extended Q&A

There is not a minimum number of people with a particular disease to justify development of a gene therapy and the initiation of a clinical trial. There have been gene therapy clinical trials that have initiated to treat only one or two participants. With a low number of participants, these trials are often structured on a compassionate use basis as the person has no other treatment options. To get a gene therapy to FDA approval, a greater number of participants are needed to have enough data that supports the drug has enough benefit and is safe. The number of participants needed to show that varies from disease to disease and there is not a set minimum number. Unfortunately, research takes resources (grants, trained scientists, valid in vitro and animal models, and participant volunteers). Those are more important driving factors. Disease frequency does drive interest and financial support for sure, but there is no minimum.

Gene therapies, in their current state have shown the greatest success in genetic diseases, especially those with a known single gene mutation (or variant). Genetic diseases are an ideal target application as seen through the current gene therapy platforms that have been developed for delivering single therapeutic transgenes.  

To date, gene therapies show varying effectiveness in patients as each drug and each disease are different.  Some are highly impactful on the quality of life for a person and can halt or slow disease progression, such as giving a person the ability to function in ways they otherwise would not have been able to. Researchers continue to develop new technology and improve the effectiveness of these drugs so that potentially one day we can make fully curative gene therapies for many diseases. 

To best manage expectations related to gene therapy, it’s important to understand that developing gene therapies takes time and tremendous resources.  Each disease is different and while there a few gene therapies that have been developed and reach patients in a shorter timeframe, most gene therapies may take years before they are safe and potentially effective enough to be tested in humans in clinical trials. Also, understand that these treatments are not cures. Many clinical trials are based on promising preclinical results, but do not guarantee that they are going to have positive outcomes for you or your loved ones. Clinical trials are investigational, meaning that the investigators are still trying to understand how safe and effective the treatment is. Finally, not all people with the disease will be eligible to receive a gene therapy. A trusted healthcare professional or member of the clinical trial research team should be consulted to help make this decision.  

Gene knockdown therapies have been approved. For example, Patisiran (Onpattro) is a therapy based on siRNA approved by the FDA for treating polyneuropathy and is marketed by Alnylam. Additionally, there are a class of drugs called antisense oligonucleotide (ASOs) that can knock down gene expression and there are multiple FDA-approved ASO drugs. These approved knockdown approaches do not use a vector and will be cleared by the body over time. As such, these therapies need to be reinjected every three to four months to maintain their effectiveness.  

These approaches are sequence specific. Most of your genes are unique from one to another. This uniqueness allows gene knockdown approaches to be designed so that they can only knock down the gene target, and not other gene transcripts. Strategies are tested rigorously for non-specific knockdown.

Immunological diseases are on the horizon for gene and cell therapies. In fact, the first demonstration gene therapy success was for severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID).  A person with the disease, Ashanti Desilva, was treated at age four and received this breakthrough gene therapy in 1990. She is still alive and well today! 

Yes and no. The COVID-19 vaccines have shown the power of LNP for delivering nucleic acids for therapy; in this case, an RNA payload to express a foreign protein to vaccinate against SARS-CoV-2.  However, the doses to achieve vaccination is comparatively lower. To achieve therapeutic levels for treating genetic diseases it takes much higher doses. Also, depending on the type of treatment delivered by LNP, such as an RNA therapy, multiple injections may be needed for the lifetime of a patient to maintain the therapeutic effect. This need presents other manufacturing burdens and requires re-evaluating toxicities, both long term and short term.

There are many! This is a rapidly evolving field with an extensive amount of research and development occurring. If you'er interested in staying up to date on the latest research and technology in the field, please register for our 25th Annual Meeting! The hybrid meeting May 16-19 is the best place to learn from thousands of the field's professionals; attend in person in Washington, D.C. or virtually. You can also follow ASGCT on Twitter.