"We are still waiting for our home run in cardiovascular cell and gene therapy," the panel's moderator, Dr. Monica Shaw, said. Shaw is the vice president and head of the Cell and Gene Therapy Center of Excellence at Iqvia.

Heart disease is the leading cause of death in the U.S. and affects people all ages, including children born with fatal genetic diseases.

"We believe that the time is now for novel approaches for heart disease," according to panelist Faraz Ali, CEO of Tenaya Therapeutics, which develops gene therapies for rare genetic disorders and for more prevalent heart conditions. "There are genetic forms of disease [with] ... incredible unmet need, including ... children who are dying within the first few weeks or months, where the science has arrived to do something that could save their lives."

Mortality rates have not improved for patients in the past 30 years, other panelists noted.

"I've been involved in medical device development and cell therapy development to treat cardiac disease since 1992," according to panelist Michael Scott, PhD, vice president of cell therapy medical devices at Novo Nordisk. "Almost 30 years ago, the mortality at five years after diagnosis was around 50%. If you look at that number today, it's about the same, despite all the advances that we have made as an industry ... we have to move the needle on this disease."

The panelists spoke on lessons learned and addressed some of the key challenges and opportunities that lie ahead for novel therapies.

Learning from the past

Gene therapy has a "checkered history," Ali said. As an example, he cited Celladon, whose Mydicar product failed in clinical trials.

"Celladon ... advanced a product to use AAV [adeno-associated virus] gene therapy to add the SERCA2a gene to the myocardium [to] try to address heart failure," Ali said. "That had early promising results and then flamed out, I think, in phase II, but we learned a lot through that experience."

One lesson learned was how important it is to lock down the process to avoid changing the product.

"Back in the day, we didn't appreciate how important it was to really lock down your process and how changes to the process can really fundamentally change the product," Ali said. "Celladon changed our process from phase I to phase II and that resulted in a different empty to full capsuled ratio and other differences in the product attributes."

The field is now on a firmer foundation in terms of manufacturing, thanks to progress in viral vectors, Ali noted.

"The first-generation efforts were using AAV1 and AAV2," said Ali. "But now we know that other vectors like AAV8 or 9 have significantly better tropism for the heart and do a significantly better job of penetrating the myocardium, so vectors certainly help in manufacturing."

Ali also cited changes in the manufacturing technologies themselves over the last decade.

"We now have cardiac-specific promoters, and we have the ability to improve on cardiac-specific promoters to really exquisitely ensure expression within the heart versus other organs," Ali said. "Even within the heart, we now have the ability to target, say, the cardiac fibroblasts versus the cardiomyocytes and to dial up or down the expression of a gene of interest within the heart."

Multiple challenges

Cardiovascular cell and gene therapies share some of the same challenges that plague the general cell and gene therapy space, according to panelist William "BJ" Lehmann, interim CEO at clinical-stage biotechnology company Athersys.

"First, there are common challenges for all cell therapies that are relevant here," Lehmann said. "You've got to be able to demonstrate that your cell has the targeted effect, and you've got to be able to characterize that well -- very critical from a regulatory perspective."

In addition to manufacturability, Lehmann named deliverability as a key concern in the cardiovascular space, citing the development of Athersys' microsyringe heart delivery mechanism.

"I think [delivery] is a key challenge, and I think it's critical to success," Lehmann said. "We've developed an approach where you can deliver a relatively, I call it [a] 'modest' number of cells, 50 to 100 million cells, and we've had some pretty promising signals from the early clinical development, and I think it's got potential."

Transformative technologies

In the face of stagnant survival rates, patients desperately need a breakthrough in cardiovascular cell and gene therapies, the panelists agreed.

A therapy like a left ventricular assist device (LVAD) for patients who have reached end-stage heart failure is both expensive and can diminish quality of life, noted panelist Jordan Lancaster, PhD.

Lancaster is the co-founder and CEO at Avery Therapeutics, which develops tissue-engineered products; its lead product, MyCardi, is being developed to treat heart failure.

"We'd love to be developing therapies that really, completely eliminate life with an LVAD ... wonderful lifesaving technologies, but quality of life on the LVAD is terrible," Lancaster said. "You're constantly in and out of the hospital, the cost is very expensive to everybody ... not a great situation to be in. How can we ... send those patients on a different trajectory?"

"These really can't be small steps forward," Lancaster said. "These technologies really have to be transformative."

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