From The Editor | March 27, 2024

Inside Tenaya Therapeutics' AAV9-Based Gene Therapy


By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

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Tenaya Therapeutics is a South San Francisco-based clinical stage biotech committed to developing curative therapies that address the underlying drivers of heart disease. The company recently made headlines for its AAV9-based gene therapy being developed for the treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by Plakophilin-2 (PKP2) gene mutations. Tenaya’s TN-401is designed to deliver a functional PKP2 gene to heart cells where it works to restore normal protein levels to halt or even reverse disease after a single dose. To learn more about Tenaya, its current pipeline, its reasoning for AAV9, and more, I talked to Tim Hoey, Ph.D., Chief Scientific Officer at Tenaya Therapeutics. Here’s what he had to say.

Tell us about Tenaya Therapeutics and its current pipeline.

Tenaya was founded with a singular focus to discover and develop new medicines aimed at the underlying drivers of heart disease and we have built a pipeline of novel candidates with diverse treatment modalities for rare genetic cardiomyopathies disorders and more prevalent forms of heart failure. Our clinical-stage pipeline includes two gene therapy candidates which use adeno-associated virus serotype 9 (AAV9) to deliver a functional gene to heart muscle cells. We’ve utilized our capabilities in identifying new targets for the discovery of a small molecule that shows promise in a common form of heart failure. Tenaya also has multiple early-stage programs progressing through preclinical development.

  • TN-201 is our lead gene therapy for myosin binding protein C3 (MYBPC3)-associated hypertrophic cardiomyopathy (HCM). TN-201 is designed to deliver a working MYBPC3 gene to cardiomyocyte cells to produce a key protein needed to regulate the contraction of the heart. In October 2023, the first patient was dosed in our MyPEAKTM-1 Phase 1b clinical trial, a multi-center, open-label, dose-escalation trial designed to assess safety, tolerability and clinical efficacy of a one-time intravenous infusion of TN-201. Tenaya anticipates sharing initial safety, biopsy and biomarker data from the first cohort of patients in MyPEAK-1 trial in the second half of 2024.
  • TN-401 is our AAV9-based gene therapy for Plakophilin-2 (PKP2)-associated arrhythmogenic right ventricular cardiomyopathy (ARVC). PKP2 mutations are the most common genetic cause of ARVC, and result in a loss of key proteins needed to maintain the structural integrity and cell-to-cell electrical signaling of heart muscle cells. Tenaya is on track to begin dosing in the RIDGETM-1 Phase 1b clinical trial of TN-401 in the second half of 2024. RIDGE-1 is a multicenter, open-label, dose-escalation trial designed to assess safety, tolerability and clinical efficacy of a one-time intravenous infusion of TN-401 for the treatment of ARVC caused by mutations to the PKP2 gene.
  • TN-301 is a small molecule HDAC6 inhibitor that has shown potential for the treatment of heart failure with preserved ejection fraction (HFpEF) in preclinical studies. At the 2023 Heart Failure Society of America Annual Scientific Meeting, Tenaya shared positive clinical data for TN-301 from a Phase 1 study in healthy participants, demonstrating tolerability at a wide range of doses studied, potential for once daily dosing, target engagement and selectivity for HDAC6.

Why is gene therapy a viable option to treat heart disease?

In diseases where a single genetic mutation results in a loss of function, gene therapy offers an elegant way to treat or prevent the condition by delivering a working gene into a target cell. Tenaya’s gene therapy candidates use an AAV vector to deliver a working gene -- MYBPC3 for HCM or PKP2 for ARVC -- where it can produce the deficient protein with the intent of normalizing the dysregulated heart function underlying the condition. Unlike currently available treatments for heart diseases, which typically attempt to manage symptoms, gene therapy offers curative potential with a single dose.

What is ARVC, and how may Tenaya’s gene therapy, TN-401, treat it?

ARVC (also known as arrhythmogenic cardiomyopathy, or ACM), is a rare, progressive heart condition. The most frequent cause of the disease is mutations in the desmosomal gene, PKP2. The PKP2 protein is needed to maintain the integrity of connections between heart cells, and the lack of protein leads to dysregulated cell-to-cell signaling and a loss of overall tissue strength. The result is frequent irregular heart rhythms, called arrhythmias, which can lead to sudden cardiac arrest and sudden cardiac death. Over time, the heart muscle becomes weaker, healthy cardiomyocytes are replaced with fat and scar tissue and as the muscle weakens the disease may progress to heart failure.

ARVC remains a significantly under-recognized heart disease, with the lack of treatments leaving patients grappling with unacceptable quality of life and the burdens of living with an ICD. It is also a hugely underdiagnosed heart disease, with many cases going undetected until sudden cardiac arrest – or sudden cardiac death - strikes.

TN-401 is an AAV9-based gene therapy designed to deliver a functional PKP2 gene to those with ARVC due to the mutation and produce the missing PKP2 protein. In our preclinical studies using a knock-out mouse model of disease, AAV9:PKP2 gene therapy was able to prevent disease onset when administered before symptoms emerged and to halt disease progression when administered after the emergence of symptoms. PKP2 protein levels were restored, the frequency and severity of arrhythmias decreased, fibrotic remodeling was prevented. Additionally, these benefits were durable – extending the survival of treated animals. Based on these encouraging results, we are advancing TN-401 into clinical trials in patients with PKP2-associated ARVC and expect to enroll our first patient in the second half of this year.

Tenaya selected AAV9 as the vector for delivery for TN-401. Why AAV9?

Early on, Tenaya invested in extensive in-house capabilities to broadly enable target identification and validation, design of AAV-based genetic medicines and in-house manufacturing. Among those capabilities is an active capsid engineering effort to identify and design vectors that can enhance the safe and effective delivery of gene therapies to target cells. In our comparisons with other available capsids, AAV9 achieved the most robust protein expression in heart cells.

We also appreciated that AAV9 is derisked by an extensive track record. The AAV9 vector has been the vector of choice in several approved gene therapies and has been used to treat thousands of people around the world with durable effects. AAV9 has been extensively studied in thousands more in clinical trials, including for heart disease where others have shown clinical evidence of its broad distribution to cells of the heart.

Share with us why Tenaya Therapeutics manufactures TN-401 and TN-201 in-house.

We know that Cell & Gene readers appreciate the importance of manufacturing. Our strategy is to have complete ownership of our process development, analytical development, manufacturing, and quality control. Both our TN-401 and TN-201 gene therapies are manufactured at our very own cGMP Genetic Medicines Manufacturing Center located in the Bay Area near our headquarters. Maintaining internalized manufacturing increases our understanding of the attributes of our drug substance and drug product, enables continuous process improvement, consistency (quality and productivity) and supports manufacturing requirements for clinical development and commercialization.