Medical Innovator: Farah Sheikh

“Often, it presents where an individual just collapses, and it can tragically result in sudden death,” Sheikh said. “Or some people can go on to form what's classically thought of as heart failure.”

Her journey as a medical innovator, striving to develop a treatment for ARVC, has led her “from bench to bedside to Wall Street,” as she shares on X/Twitter. Her passion to address this specific heart condition stems from a personal connection.

“With a family history of heart disease, I’ve always had a strong pull towards exploring the therapeutic applications of my foundational research in cardiovascular sciences,” Sheikh said. “And unfortunately, with ARVC, I do have someone in my life affected by it. Coincidentally, as they underwent diagnosis, I happened to be studying the genes that may drive the disease.”

In a significant proportion of ARVC patients, this hereditary disease is rooted in a mutation in the plakophilin-2 (PKP2) gene, which encodes a critical protein important in a structure known as the desmosome, which ensures the mechanical connectivity of heart muscle cells to one another.

Investigation revealed that the PKP2 mutation resulted in the emergence of an altered form of the PKP2 gene, while the healthy version was absent. Moreover, Sheikh and her team discovered that the challenge resided in the total quantity of PKP2 protein, both mutated and normal. This insight prompted them to prioritize the development of strategies to boost production of the healthy PKP2 gene and its desmosome-building abilities. Sheikh and her collaborators outlined a potential therapy in a recent paper in Nature Cardiovascular Research.

A primary objective of Sheikh’s medical research is to make therapies available to the public through entrepreneurship. She worked with the UC San Diego Office of Innovation and Commercialization to patent her discoveries. She subsequently spearheaded the establishment of a start-up company, ARVC Therapeutics Inc., which later merged into Stelios Therapeutics, the company acquired by LEXEO.

“I'm very fortunate because UC San Diego has a strong entrepreneurial spirit,” Sheikh said. “I’m aware of other investigators also launching spin-off companies from their labs.”

She said critical thinking among researchers often engenders creativity, especially when pursuing lines of inquiry that are contrary to “settled science” and even dogma. Sheikh gave an example from her AVRC investigation in which her team discovered that contrary to many of the prevailing hypotheses, even the mutated form of PKP2 still did its job — if there was enough of it in the cell.

“So, you have a completely different treatment strategy if one goes after removing the alternate or mutated form, given our demonstration that this form is not toxic as previously believed,” she explained.

Sheikh juggles various roles at UC San Diego, balancing her time between research, teaching, service on various committees, as well as mentoring a diverse team of trainees in her lab — a group that spans the spectrum of academia from project scientists and post-doctoral researchers through graduate students and even undergrads. Reflecting on the dynamic nature of her responsibilities, she says that if her UC San Diego life as a researcher-educator-mentor-entrepreneur-collaborator-consultant were plotted out as a pie chart, each day would have a different pie.

“Most of my effort is in the research domain and working with the amazing trainees I have,” she said, “seeing their delight in the results and in moving the needle forward.”

When Sheikh helped to ring the bell at NASDAQ for LEXEO, she also was moving the needle forward and helping to ring in a new era for innovation in cardiac gene therapy. “I think we are at a pivotal time right now where gene therapy can be used safely in patients,” she said.

Sheikh’s ARVC approach is based on engineering a non-replicating virus that targets the PKP2 gene. While many labs target other hereditary diseases use a similar approach, her strategies are uniquely crafted to address the complexities of ARVC. She points out that concerns from previous studies about safety and side effects such as liver toxicity have largely been laid to rest simply by lowering dosages.

“I think we’re at the prime time for using this technology,” Sheikh said. “For genetic disease, where a single gene may be responsible for driving a particular hereditary condition, we have all the data in hand at this stage to show that we can begin to address it.”