Differences Between a Gene Therapy Clinical Trial and a Cure

Differences Between a Gene Therapy Clinical Trial and a Cure

TL;DR: Clinical trials are complex, have potential risks associated with participating, and can take years to complete. Clinical trials assess a potential new treatment’s safety and efficacy before FDA approval. Eligibility criteria for clinical trials will be established and endpoints will be defined and measured to determine treatment success. It is important to note that gene therapy isn’t a guaranteed cure; individual responses vary and long-term impacts are still being understood. Once a clinical trial has finished, the data collected from those who received gene therapy will help researchers better understand this new therapeutic technology.

Differences between a clinical trial and a cure/medical treatment

A clinical trial is a research study required by the FDA before a drug is available on the public market. The purpose is to test the safety and ability of a new therapy to improve a specific disease state or “indication”. Based on clinical trial data, the FDA decides if a drug is approved or not. To say that an FDA-approved drug works and a rejected drug does not work, however would be limiting. Clinical trials, especially in the case of rare diseases and gene therapy, are not so black and white. In rare disease clinical trials with patients that have varied experiences with the same condition, it can be difficult to measure whether a treatment is effective. This article will explain how clinical trials are set up, the unique features of testing new treatments in rare conditions, potential differences in receiving gene therapy post-approval, and set expectations around the potential of gene therapy.

What can I expect in a gene therapy clinical trial?

Design of a clinical trial for gene therapy 

Clinical trials are divided into three phases. Classically, Phase I is designed to assess safety of the intervention in healthy individuals, Phase II is designed to test the safety and dosage in individuals with the disease, and Phase III assesses efficacy with a larger group at the determined dose. Sometimes these trial phases are combined for logistical or ethical reasons, as is often the case for rare conditions and for gene therapy.

Gene therapy trials for rare diseases often use a Phase I/II where safety and efficacy are tested at the same time. Due to the risks of gene therapy and the lack of alternative care options for many rare diseases, gene therapy is tested in people who have the disorder and not in unaffected individuals. Testing for safety in unaffected individuals places undue risk on them, excludes them from receiving gene therapy in the future (more on this below), and delays individuals with the disorders from receiving a treatment that may benefit them. More information on trial design is available from the American Society for Gene and Cell Therapy (ASGCT): Clinical Trials 101.

Trial eligibility

To participate in a clinical trial, patients must meet certain eligibility criteria. There are factors that are required for trial participation, called “inclusion criteria”, and factors that make an individual ineligible for trial participation, called “exclusion criteria.” 

Inclusion criteria may include having a known genetic mutation that causes the condition, being within a certain age group, having specific disease symptoms (i.e. seizures), or being in a certain state of disease progression.

Exclusion criteria may include ability to participate in tests for trial outcomes (e.g. blood draws, EEG), having a secondary illness, or inability to participate in follow-up visits. In the case of gene therapy, there will be a test to look at the level of antibody against the viral vector used to deliver genetic material. The level of antibody, called an “antibody titer” must be below a certain threshold. Otherwise, there is high risk of a severe immune response, posing serious safety concerns and causing the body to reject the gene therapy. More information about antibody titers can be found in this informational sheet from Sarepta and in a recorded conference or seminar from NYU Langone.


Based on pre-clinical studies in animal models, researchers determine a low-dose and a high-dose to test the safety and efficacy of the gene therapy. The low-dose arm of the clinical trial is done first because it is less likely to have side effects. However, a low-dose may not be as effective in treating disease symptoms. The high-dose arm follows if the low-dose shows no major safety concerns. A higher dose poses greater risk, but this dose may more effectively treat symptoms. There are many factors considered when determining high- and low-dose arms, including risk profiles and timing.


Clinical trials look for changes in physiological traits, which are called “endpoints.” Endpoints are carefully selected for a clinical trial based on what may indicate a therapy had an impact, what may indicate decreased disease symptoms, and what can be quantitatively measured (scientists like numbers!). In essence, an endpoint is what researchers look at to determine if the therapy “worked.”

Which endpoints are important to researchers may not be the same ones that are important to patients and their families. For example, SLC13A5 gene therapy is designed to increase the level of the protein that moves citrate from outside the cell to inside the cell. Researchers may look for a change in the amount of the transporter, but this sort of endpoint, called a “surrogate endpoint” does not necessarily indicate any change in quality of life. A meaningful endpoint to patients may look like measuring seizures, hospitalizations, or sleep, but these endpoints are often more complex to measure or may take more time to assess. A surrogate endpoint can be an easy way for researchers to measure the potential for impact on quality of life. It is possible that a therapy “works” according to patients and their families, but the endpoints considered by the FDA do not meet their standards for approval. Patient involvement in the trial design process and participation in natural history studies are two strategies to ensure the endpoints are satisfactory for everyone.


When viruses enter the human body, our immune system may recognize them as foreign and potentially dangerous and initiate an immune response to remove them. In day-to-day life, the immune response is important in fighting off viral colds and keeping us feeling well. However, when a virus is used to deliver genetic material in gene therapy, this same response is detrimental and potentially life-threatening. To reduce the chance of a severe immune response, researchers use two different strategies. The first is ensuring the body does not have antibodies against the viral vector via an antibody titer test (discussed in trial eligibility) meaning our immune system does not recognize this virus. The second strategy is suppressing the immune system using a course of immunosuppressant drugs called glucocorticoids. Patients receiving gene therapy may take immunosuppressant drugs for a number of days before gene therapy infusion. Nearly three-quarters of clinical trials with AAV9 and one-third of trials in the CNS included immunosuppression.

How might receiving gene therapy in a clinical trial differ from receiving it after it is approved? 

Better Understanding

A clinical trial is the first time a new therapeutic is tested in human beings. While researchers and clinicians have done extensive studies and have reason to believe a new therapy is safe and will be beneficial, we simply do not know for sure until we try. This is the purpose of a clinical trial. This provides a better understanding of the effective dose, side effects, and which disease symptoms may benefit, and to what extent.

Gene therapy is a new therapeutic, with the first approved in 2017. The field still does not understand all of the long-term impacts of receiving gene therapy. There are concerns that gene insertion into our DNA may change other genes involved in the development of cancer. Researchers are also unsure how long gene therapy may work, with the potential that its effects decrease over time. The field is working to understand what factors go into this, and what this time frame might be. In cells with limited turnover like in neurons in the brain, this is less of a concern.


After a therapy is approved, the dosing amount will be determined and indicated on the label. There will not be a low-dose or high-dose as within the clinical trial.

Available locations

Once a gene therapy is approved it may be available at more locations. However, receiving gene therapy is a medically intensive process and few locations are trained to offer gene therapy. A list of medical centers that offer gene therapy can be found here.

Label expansion

In time, there is potential for label expansion, meaning the therapy is approved for more individuals. This may be increasing the age range where patients can receive the treatment and it may add indications it can be used to treat.

An approved gene therapy is not a cure (probably)

The word “cure” has different meanings for different people. Is it remission with no more seizures forever? Is it a cure if symptoms are in remission for a time, but ultimately recur? Does significant improvement sound like a cure, even if your child is still impacted? What if it stops disease progression, but the current symptoms remain? This is important to consider for genetic disorders with childhood onset.

There have been instances where gene therapy looks like a cure, for example where hemophilia patients no longer take their clotting factor. However, it is important to note that this is not the case for all patients who received the same treatment. Cases like this are thrilling and give hope for the possibilities of gene therapy, but the technology is not able to reliably or predictably offer remission for those who receive it.


Clinical trials for rare disease are complex and take years to complete. Selecting endpoints is challenging due to the diversity of clinical manifestations and differences between what is easy to measure and what is most impactful on quality of life. Clinical trial participation is a chance to receive a new therapy sooner, though there is higher risk since it is the first time it is tried in humans. It is important to consider your personal motivations and needs for clinical trial participation and what outcomes are meaningful to you and your family. What looks like a “cure” is individually defined and patients will not all respond the same to gene therapy. After a clinical trial is complete and as more data is collected from those who have received gene therapy, we will gain a better understanding of this new therapeutic technology.


Clinical trials process. ASGCT. (n.d.). https://patienteducation.asgct.org/gene-therapy-101/clinical-trials-process 

Shen, W., Liu, S., & Ou, L. (2022). rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis. Frontiers in Immunology13, 1001263.

Verbeeck, J., Dirani, M., Bauer, J. W., Hilgers, R. D., Molenberghs, G., & Nabbout, R. (2023). Composite endpoints, including patient reported outcomes, in rare diseases. Orphanet Journal of Rare Diseases18(1), 262.

This article was written by Zollie Yavarow, PhD, MA, a Postdoctoral Fellow at COMBINEDBrain and independent consultant with Zaris Consulting. She earned her PhD in Pharmacology and MA in Bioethics and Science Policy from Duke University in 2022. Bringing nearly a decade of experience at the lab bench studying mechanisms of rare and neurological disorders, Dr. Yavarow utilizes her background to navigate the complex landscape of developing gene therapies for rare disorders as a patient advocate.

Figures were created using BioRender.com.

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