Editor’s note: Recently, Cynthia Waldman of HCMBeat had the chance to interview Dr. Laura Robertson of Tenaya Therapeutics . Dr. Robertson is charged with leading the clinical development program for Tenaya’s experimental gene therapy treatment for HCM.
You have probably read about gene therapy and wondered whether it could ever be used to treat hypertrophic cardiomyopathy. HCMBeat has written several stories about the growing field of gene therapy, shining a light on the researchers and companies focused on this effort.
You can read these previous stories here:
Times of London Shines Light on HCM
Gene Therapy – Is a Cure for HCM Around the Corner?
Tenaya Therapeutics Gets Go-Ahead for HCM Gene Therapy Trial
Gene Therapy – Is HCM Cure Possible?
HCM Genetics Discovery by British Researchers
Below you will find an exchange of questions and answers between HCMBeat and Dr. Robertson. They provide insight into how gene therapy might one day actually cure HCM. Only time will tell, but these therapies could potentially provide a future for our children and grandchildren free from the burden of HCM.
1. When was Tenaya Therapeutics founded? What other conditions has the company been focused on?
Tenaya was founded in 2016 to develop medicines that address the underlying causes of heart disease. In addition to our lead gene therapy program for MYBPC3-associated HCM, we have a small molecule therapy being developed for the potential treatment of heart failure with preserved ejection fraction (HFpEF) and a gene therapy candidate being developed for arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by PKP2 mutations. Our scientists are continuously striving to learn and discover new therapeutic compounds. As a result, we have identified several new genetic targets that may be of interest in treating cardiomyopathies and other heart diseases in the future.
2. How did Tenaya become focused on HCM and the MYBPC3 gene?
Changes in the MYBPC3 gene (often called mutations) are the most common genetic cause of HCM. MYBPC3-associated HCM is also an example of a condition where the disease-causing mutation is isolated to a single gene. Disorders caused by mutations in a single gene – versus those caused by multiple genetic or environmental factors – are the best candidates for gene therapy, since the goal of treatment is to replace the disease-causing gene with a working gene. That combination of a significant unmet need and a path to creating a genetic medicine that could potentially address the underlying cause of disease aligned perfectly with our mission to transform and extend lives through the discovery, development and delivery of potentially curative therapies targeting the underlying causes of heart diseases.
3. How do genes cause hereditary cardiomyopathies like HCM?
When a change or mutation happens in a gene it can cause that gene to not behave the way it’s supposed to. For example, the MYBPC3 gene creates a protein that helps the heart to squeeze (or contract) and relax appropriately with each beat. When there is a mutation in the MYBPC3 gene, that protein is not produced and so the heart doesn’t function correctly. And because every child born gets one copy of each gene from each parent, these mutations can be passed down. Most people with MYBPC3-associated HCM have one healthy gene and one that doesn’t function properly. The healthy gene does its best to compensate, but it just can’t produce enough protein for the heart to function normally and so HCM develops. The goal of our investigational TN-201 gene therapy is to deliver a healthy gene to supply the necessary protein and restore protein levels to meet the demands of the body.
4. What results have been seen in mice treated with TN-201?
The results of our preclinical studies, in which a healthy MYBPC3 gene was delivered to heart cells to replace the activity of the mutated gene, were positive and led us to develop a plan for clinical testing. We studied mice in which we “knocked out” their MYBPC3 gene entirely. They produced no myosin binding protein and consequently they were very sick and were not expected to live more than several weeks. Once they received a single dose of a mouse version of our TN-201 gene therapy, their condition became similar to healthy mice: cardiac function improved, hypertrophy was reduced, and survival was extended to normal lifespans. We were so encouraged by the results in mice that we decided to pursue the next steps in developing TN201 as a potential treatment for MYBPC3-associated HCM and we are now advancing the product candidate into human clinical trials.
5. How long did it take to see results in mice? Did changes in the heart continue over time?
In mice, we saw improvements in heart function within weeks of administration of the gene therapy. It’s not instant; the new, working gene needs to enter cardiac cells so that it can begin producing protein, but once that happens, we saw that the disease symptoms in the heart improved and those improvements continued for the lifespan of the mouse.
6. Have any gene therapies been approved by the FDA to date?
Yes, there are several gene therapies that have now been approved in the U.S. and EU. and more than 5,000 people around the world have received gene therapy, for diseases such as spinal muscular atrophy, hemophilia type b, genetic eye disease, and several types of cancers. More gene therapies are being considered for approval, and still more are currently in clinical testing.
7. Have gene therapies ever been used for the treatment of any heart diseases?
Not yet, though the first gene therapy for a heart condition is being tested in early clinical trials now. Based on the evidence generated to date, we know it’s possible to deliver a gene therapy to target heart cells where the new, healthy gene can produce the necessary protein in order to address the underlying cause of disease.
8. How does TN-201 work to address HCM caused by genetic mutations?
TN-201 gene therapy is designed to deliver a healthy, working MYBPC3 gene via a one-time intravenous infusion in the arm. The gene therapy contains instructions that help deliver it to heart cells, where it is incorporated into the cardiomyocyte cells and can begin producing the necessary myosin-binding protein that enables the heart to function normally.
9. How is gene therapy different than other available treatments?
Ideally, gene therapy is a one-time treatment with long-term results, intended to address the underlying genetic cause of the disease. By delivering a healthy working gene to replace the nonworking gene, we are hopeful that normal function can be restored. In clinical trials, we need to prove that our gene therapy will work as anticipated and provide long-term changes in how the heart functions and the patients feel and function. In contrast to current daily medications that manage the symptoms that result from HCM, gene therapy aims to treat the underlying cause of the hypertrophic cardiomyopathy. Even new medications for HCM require patients to take daily pills, since they do not change the underlying cause of HCM.
10. When and in what centers will the currently planned Phase 1 clinical trial be taking place?
We are looking forward to beginning to dose the first patients in our MyPeak-1 clinical trial of TN-201 soon – probably in late summer or early fall of this year. Many leading HCM experts are excited by the prospect of what gene therapy may be able to accomplish for patients. We plan to conduct the trial at major cardiology centers across the U.S. More information about our MyPeak-1 clinical trial is available at Clinical Trials.gov
11. How is TN-201 delivered to the patient? Is the single infusion given through a vein in the arm, or is it delivered directly to the heart?
The gene therapy is a solution that is delivered intravenously in a single infusion of therapy given through a vein in the arm. The working MYBPC3 gene is enveloped in what’s called a “vector” that allows it to enter into cells. Within that envelope, we’re able to add certain elements that act like the address – directing the vector containing the healthy gene to the heart cells where it’s needed. Thousands of these genetic packages are included in one single infusion.
12. What are some of the risks associated with gene therapy? Is it safe?
The main risks of gene therapy are related to immune system reactions. Because viruses are very good at getting into cells, the shell of a virus is used as the envelope to deliver gene therapy. Although the viral vector cannot cause disease, the immune system may still mount a reaction that could make the gene therapy ineffective or even make a person feel sick. There is also a risk that in spite of being engineered to target specific cells, the viral vector could go to healthy cells and cause damage that might result in illness. Gene replacement therapies, such as TN-201, are intended to prevent or treat disease following a single dose, so there’s also a risk that if it doesn’t work, a patient would be unable to try gene therapy again. While thousands of patients have received gene replacement therapy using viral vectors either as part of clinical studies or as an approved treatment for their genetic condition, there may still be some risks that have not yet been discovered or that may be associated with a specific condition. The primary purpose of the MyPeak-1 clinical trial is to evaluate doses of TN-201 that we believe can be effective in treating disease for safety and tolerability by patients. We have worked very closely with the FDA to design the study and ensure patient safety through close monitoring of patients and the administration of certain medications intended to prevent potential reactions.
13. How many patients do you plan to enroll in the Phase I trial?
We will start by enrolling at least six people with nonobstructive HCM into the clinical trial and may expand to enroll up to 15 patients.
14. Why are you only enrolling patients in the clinical trial who have implantable defibrillators (ICDs)?
It’s one more way to monitor for safety in our initial cohorts of patients. Having an ICD in place also allows us to collect more data about how the heart functions in this early-stage trial.
15. How often will patients be followed in this clinical trial?
Initially, there will be a lot of monitoring to ensure patient safety and to understand how this new treatment is working, but over time those requirements become less and less frequent. Since this is a first-in-human dosing trial, participants will be hospitalized for safety monitoring for the first week after the intravenous gene therapy. As with other gene therapies, recipients are given a temporary course of immunosuppression medications to reduce the possibility of an adverse reaction to the therapy. Participants will visit the clinic regularly for monitoring during the first few months of the trial. The cardiology clinic visits then become less frequent for the remainder of the first year after treatment. There are five cardiology clinic visits over the next four years for necessary long-term safety follow-up.
16. Assuming all goes according to plan, how long do you think it will take for this drug to be FDA approved and ready to be prescribed to patients?
That’s the big question. We can’t say for sure, but it usually takes several years of clinical testing to ensure that a treatment is both safe and effective. While TN-201 has not been approved by the U.S. Food and Drug Administration or any other country’s health authority or regulatory agency to date, at Tenaya, we are committed to getting treatments to patients as expeditiously as possible while ensuring that the treatment is not only safe but also provides an effective treatment that measurably improves a patient’s quality of life.
17. Are you planning to develop therapies for other HCM causing genes like MYH7 which is another common HCM gene?
We are exploring potential treatments for other cardiomyopathies. Some genetic mutations are more complex than others and may be better suited to other types of therapies, like gene editing. Because of the large size of the MYH7 gene, it may be better addressed through gene editing approaches. We are exploring treatments for many other genetic cardiomyopathies.
18. Where can people go to learn more?
The MyPeak-1 clinical trial is listed on clinical trials.gov (ClinicalTrials.gov Identifier: NCT05836259). You can also check out Tenaya’s website for more information or you can email Tenaya directly at:
patient.advocacy@tenayathera.com
Laura Robertson, M.D. is a pediatric cardiologist who trained at Johns Hopkins in Baltimore, Maryland. As a Professor of Pediatrics at University of California San Francisco for 15 years, she cared for children with congenital and genetic heart diseases. Since 2016, she has worked to develop treatments for cardiomyopathies. Dr. Robertson came to Tenaya Therapeutics following earlier stints at both MyoKardia and Cytokinetics. She currently leads the clinical development program for Tenaya’s first cardiac gene therapy treatment for MYBPC3-associated HCM.
HCM Beat 
I just read the article on the HCM Beat website about gene therapy for HCM, and it’s truly fascinating. The potential breakthroughs discussed in the interview with Dr. Laura Robertson are incredibly promising. Gene therapy could revolutionize the treatment of hypertrophic cardiomyopathy and provide long-term solutions. It’s inspiring to see companies like Tenaya Therapeutics leading the way in this field.
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