Continuing Innovation on Modality-Specific Technology for Cardiovascular-Targeted Genomic Medicines

Faraz Ali, MBA

Tenaya Therapeutics is a biotech company focused on the development of genomic medicines for heart diseases. In addition to therapeutic candidates themselves, though, the company is also working on innovations to various aspects of gene therapy and gene-editing as modalities, such as capsid-design and manufacturing.

At the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD, Tenaya presented 7 posters covering their broad-ranging efforts. At the conference, CGTLive spoke with Faraz Ali, MBA, the chief executive officer of Tenaya Therapeutics, to learn more.

CGTLive: Can you give some background info about Tenaya Therapeutics?

Faraz Ali, MBA: Tenaya is a clinical stage gene therapy company and we have 2 genetic medicines in the clinic for genetic forms of cardiomyopathy: TN-201 for the leading genetic cause of hypertrophic cardiomyopathy and TN-401 for the leading genetic cause of arrhythmogenic cardiomyopathy. We're not actually presenting anything on those programs at this conference. Those are clinical stage programs—we're very excited for them, and that's sort of where the field is going, and we're excited to be part of it.

What is Tenaya presenting at ASGCT’s 2024 Meeting?

At this conference, we have 7 posters and it really I think captures sort of where we've been and where we're going. We are committed to platform enhancements that will enable the field of precision genetic medicines for cardiovascular disease. That includes breakthroughs in capsid-engineering, in promoter-engineering, and in manufacturing—all through the lens of trying to widen the therapeutic index, lower the cost of goods, and improve the possibility of delivering the hope of these therapies to patients.

We have 1 poster that just compares head-to-head various capsids—parental capsids, actually—AAV9, AAVRh74, and AAVRh10... It's the first time to our knowledge that somebody's been so systematic in showing the expression of these capsids in the right cells of the heart (the cardiomyocytes); a head-to-head comparison in mice, nonhuman primates (NHPs), and also a head-to-head comparison in a disease model for gene editing—all of which is showing that AAV9, of the parental capsids today, seems to have the best profile for expressing in the heart. (We're using AAV9 in our clinical stage programs TN-201 and TN-401.)

Then there's a poster about capsid-engineering. We have already screened to date more than a billion variants from 30 diverse libraries... In multiple species, in human cells, mice, and NHPs. We know that we can do better than AAV9 and we've been very pleased with what we've achieved in our capsid-engineering efforts to date, but we keep on pushing the boundary. Why we need to do that is to increase the diversity of the libraries. We have a poster showing how we've increased the diversity of the libraries that will give yet another interesting place to start for next-generation capsid-engineering efforts.

The capsid is one part of the virus for an AAV gene therapy, but then there's the promoter and the promoter is incredibly important. That is what gives you that not only heart-specific expression, but even a target-cell (cardiomyocyte-specific) expression. We are always looking for opportunities to make promoters smaller and stronger. That allows you to have better therapies and also to carry more and more genetic material inside the AAV (which has a limited carrying capacity). One of the posters that is at this conference shows our promoter-engineering efforts and there's a highly compact, less than 300 base pair, cardiomyocyte-specific promoter that's out there that would allow us to deliver larger genes—which could be important to gene transfer efforts—but also in the context of gene-editing where there's a whole genome-editing machinery that we're trying to fit into a single AAV—having smaller, more compact cardiomyocyte-specific promoters would be helpful. We have a poster on that, as well.

We have a poster on gene-editing efforts for just for what I just talked about. There's a rare genetic cardiomyopathy for which gene-editing is the only hope and solution for those patients in need. We've presented data on that in the past, but this time we're presenting data on a next-generation effort that has self-inactivation. One of the big concerns with gene editing is long-term expression of this foreign protein in the human cells and heart—and one approach that might help with those concerns about immunogenicity and off-target effects is to limit the expression. As such, Tenaya has demonstrated that with a self-inactivating vector, we can limit the expression of the CRISPR/Cas9 protein in an all-in-one AAV gene-editing cassette without any change in what is a very robust efficacy profile for that product.

Then we have 3 manufacturing posters. Tenaya made a decision a long time ago to internalize manufacturing technology. We actually are unusual in that we've internalized both Sf9-recombinant baculovirus, as well as a HEK293. Our manufacturing products that have gone into the clinic use recombinant baculovirus Sf9 cell technology, but we're also interested in seeing whether we can prove both platforms in parallel. As such, our posters are generally capturing improvements. One is for Sf9 and 2 are for HEK, showing that with varying approaches, we can improve the yields, which is really important: You want more manufacturing at larger scales and you want to lower the cost of goods of these products over time to make them commercially viable. Those past those posters capture various efforts: a Rhabdovirus-free cell line for Sf9, which improves the yields, and a small-molecule booster for HEK, which improves the yields there. Furthermore, there’s really clever rational design, even genetic modification of the starting cell line material, that allows for higher manufacturing yields without any change in the product attributes.

So that’s quite a suite, quite a mouthful. Everything from capsids to promoters to gene-editing to manufacturing technology. They could be very collectively valuable for second generation products for our lead gene therapy programs, they could be used in our next wave of programs that will go into the clinic, and they frankly could be useful in partnerships with big pharma or other peer companies to enable their technology. That's what's going on here—quite a lot for a small company, but we're really excited.

This transcript has been edited for clarity.

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