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Gene therapy research for frontotemporal dementia: understanding the science and clinical trial considerations

Frontotemporal dementia (FTD) research suggests that genetic testing is important in notifying families of possible genetic causes of FTD early on. Once detected, patients, caregivers and physicians can develop a care plan that may involve participating in a clinical trial, where innovative approaches to alter disease progression are being tested.  

Currently, there are no approved therapies to treat frontotemporal dementia (FTD), the most common form of dementia for individuals under the age of 60. However, recent advancements in our genetic understanding of the disease alongside expanded access to genetic testing for FTD has revealed novel avenues of potentially slowing or stopping disease progression for individuals affected by this devastating disease, such as gene therapy.

Gene therapy research shows potential for slowing or stopping disease progression for many neurodegenerative disorders, including FTD. 

One of the goals of gene therapy is to introduce a healthy or functional copy of a mutated gene into a person’s cells or tissues to produce a missing or deficient protein. The majority of gene therapies being researched are intended to be one-time treatments that will last lifelong. Over the last 40 years, our understanding of genetic medicine has advanced significantly. Today, transformative gene therapies have been approved by the FDA for the treatment of certain rare diseases (like spinal muscular atrophy and retinal degeneration), and multiple other gene therapies are in different stages of clinical development, with an increasing focus on neurodegeneration. 

There are many different approaches to gene therapy currently being studied. Clinical trials may categorise gene therapies by in vivo or ex vivo treatments. In vivo gene therapies are delivered directly to the patient through an injection or IV infusion. Depending on the cells needed to treat a particular disease, an in vivo gene therapy treatment might be delivered directly into a specific part of the body, such as the cerebrospinal fluid (CSF) or brain tissue if targeting brain cells, or into the back of the eye if targeting retina cells. In comparison, ex vivo approaches involve harvesting target cells from the patient and treating them with the gene therapy first in a laboratory before transplanting them back into the body. 

Unlike gene editing—which aims to edit or alter a person’s existing DNA—gene therapy aims to introduce new DNA to a patient’s cells to potentially restore the function of a disease-causing gene.

To deliver the new DNA to the appropriate cells, both in vivo and ex vivo gene therapy approaches often rely on modified viruses called vectors, which are special carriers designed to transport genetic material to specific organs, such as the liver or brain. 

Adeno-associated viruses (AAVs) are the most commonly used vectors for in vivo gene therapy research as they are engineered to be non-replicating and not known to cause disease in humans. AAVs are intended to serve only as ‘shuttles’ to deliver the functional gene to the target cells and are expected to disappear from a person’s body after delivery. Other viruses may also be used to create vectors, such as lentivirus, which is more commonly used in ex vivo approaches. 

Alongside advancements in gene therapy research, multiple genes linked to FTD have been identified, expanding our understanding of both sporadic and familial forms of the disease. The most common genetic causes of FTD are variants in the C9orf72, MAPT, and GRN genes.

Today, there are multiple gene therapy clinical trials underway specially designed to target one of these mutations using different approaches.

Several of these studies are exploring the application of AAV gene therapy to potentially treat FTD caused by GRN mutations (also called FTD-GRN). FTD-GRN results from mutations in the GRN gene that produces a protein called progranulin that is important for breaking down cellular waste. These mutations lead to insufficient progranulin levels, which can result in the neuroinflammation and neurodegeneration observed in FTD-GRN, considered the most aggressive and rapidly progressive form of FTD.

In the case of gene therapy research for FTD-GRN, a working copy of the GRN gene is placed inside an AAV vector and injected directly into the central nervous system to deliver the new gene into target cells in the brain. Once the gene is injected into the CSF surrounding the brain, the body should have the ability to produce more progranulin, potentially altering the progression of the disease. 

Over the past decades, simply reaching the intended target (i.e. brain tissue or cells) was a major challenge for any neurological drug, due in part to the presence of the blood-brain barrier, which works to protect the brain from toxins or pathogens. While effective at protecting the brain from infections, the blood-brain barrier can also block potentially beneficial drugs or therapies from reaching the brain. Advances in gene therapy technology now allow for the efficient and widespread delivery of gene therapies to the central nervous system. 

Despite these advances, ongoing clinical trials are necessary to fully understand how different gene therapy approaches might be applied to the treatment of FTD. Through carefully designed clinical trials guided by scientific principles and informed by clinician, patient and caregiver insights, we can gain a more complete picture of the risks, benefits and potential long-term effects of gene therapy. 

Gene therapy clinical trials 

Clinical trials provide eligible patients with the opportunity to participate in an investigational treatment to determine how it behaves in the body as well as its safety and efficacy. These trials have the potential to progress scientific research being done to develop life-changing therapies for patients everywhere. There are hundreds of gene therapy clinical trials in progress for several disease types.

Before entering a clinical trial, you should first consult with your doctor to understand whether gene therapy might be right for you. Your healthcare provider can give informed advice based on your individual health and history. Genetic testing is also an important step to determining whether a person may be eligible for a particular gene therapy clinical trial as certain treatments may be mutation-specific. For those considering genetic testing, it’s important to speak with a genetic counsellor before or after getting tested, or both, to ensure you understand all considerations that may be important for you and your family. (See here for more information about genetic testing and counselling considerations for FTD.)

When considering gene therapy clinical trial participation, it is crucial to be informed of what to expect. All patients entering a trial will be given an informed consent document explaining the specific trial’s study design, time frame, schedule of assessments, potential risks and more. Participants will then undergo an initial clinical screening to determine if they meet the trial’s eligibility requirements, including whether they have the specific genetic mutation the treatment is developed to target. Screening may also include blood or urine tests to study a potential participant’s current state of health. 

Additionally, individuals should consult with their care partner(s) about the requirements of clinical trial participation and what level of commitment it may require. For example, some gene therapy trials for neurodegenerative conditions may require a study partner to attend all study visits alongside the primary participant and offer support when it comes to scheduling visits and traveling to and from the study site.

Finally, while gene therapy is intended to be a one-time treatment, clinical trials for gene therapy can last several years. The period after treatment, often called the ‘follow-up period’, is important for researchers to track the long-term safety and effects of the intervention.  

For example, one major unanswered question in gene therapy research today is how long the effects will last or whether someone may see waning effects over time. By participating in all visits for the full duration of the trial, participants can support gathering this important scientific evidence; however, such a commitment may not be feasible for every person or family and should be considered alongside other important aspects of participation. 

Learn more and get involved

Gene therapy breakthroughs present new hope for individuals and families affected by neurodegenerative diseases like FTD. If you or a loved one are interested in learning more about gene therapy research or exploring clinical trials currently underway for FTD, below are some additional resources: 

  • www.ClinicalTrials.gov: A public website that provides access to information about clinical trials for a variety of diseases. Searching for your condition of interest will return a list of studies in various stages of research, including eligibility criteria, study locations and contact information for those studies. 
  • The American Society of Gene and Cell Therapy (ASGCT): A professional organisation providing educational resources for patients and families to better understand gene therapy research. ASGCT’s patient education portal provides digestible information on several topics related to gene therapy, including how to identify an inherited disease through genetic testing. The portal offers resources on learning more about the clinical trial process, the latest research in the field and understanding the patient journey. ASGCT also has a Clinical Trials Finder to search for open trials in gene and cell therapy.
  • The FTD Disorders Registry: An online database created to advance clinical research by collecting information from those affected by all types of FTD. By signing up with the registry, participants also receive alerts when new clinical trials for FTD become available.  

Invitae’s Adult Neurodegenerative Disorders Panel offers free genetic testing and post-test genetic counselling to individuals with a confirmed or suspected diagnosis of FTD and their family members living in the US, Canada, Australia, and Brazil. More information about this program can be found at: www.invitae.com/en/adult-neurodegen/


Prevail Therapeutics, a wholly owned subsidiary of Eli Lilly and Company, is dedicated to developing gene therapy-based treatments with the potential to slow or stop the progression of neurodegenerative conditions such as frontotemporal dementia, Gaucher disease, and genetic forms of Parkinson’s disease. To learn more about Prevail, visit their website.

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