Taking gene therapy to the masses with innovations in diabetes, Alzheimer's and more

When Kriya Therapeutics raised $80.5 million in a series A funding round last May, it was as clear a sign as any that gene therapy is moving beyond rare diseases and going mainstream. The biotech is working on three gene therapies to treat metabolic diseases, including its lead asset, KT-A112, for Type 1 diabetes.

What will it take to transition gene therapy from a treatment for diseases that only affect a few hundred thousand people worldwide to Type 1 diabetes, which is estimated to affect more than 45 million? Nothing less than a complete rethinking of how gene therapies are developed and manufactured, said Kriya CEO Shankar Ramaswamy, M.D.

“Gene therapy 1.0 has been about finding a way to make the product for a very small population at a high cost and finding a way to make up the difference by charging astronomically high prices,” Ramaswamy said in an interview. “One key element that needs to be solved is making gene therapy products more efficiently, at scale, at a lower cost. We’re investing heavily in that.”

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Kriya is among a growing group of startups and academic teams working on innovative ways to bring gene therapy to the masses, attacking diseases like diabetes, obesity and Alzheimer’s.

Most of their research is still in preclinical or early clinical testing, but the scientists and entrepreneurs spearheading the effort are already thinking about overcoming hurdles they expect to face in development, regulatory affairs and manufacturing.

Kriya’s KT-A112, licensed from Universitat Autònoma de Barcelona, delivers genes to produce insulin and glucokinase and has been proven in small and large animal models to reverse diabetes with just one injection into the muscles. The company is now working on improving the adenovirus-associated virus (AAV) vector that’s used to deliver the genes.

Its scientists are running it through algorithms hoping to reduce the probability of a dangerous immune response, improve gene expression and make the therapy easier to manufacture on a large scale, Ramaswamy said. The company hopes to apply to the FDA for permission to start clinical trials before the end of 2022.

Gene therapy for metabolic disorders

A University of Pittsburgh team is also working on gene therapy to treat diabetes, but it's taking a slightly different tack. The researchers are using an AAV to deliver the genes Pdx1 and MafA directly to the pancreas. Those genes make proteins that transform pancreatic alpha cells to insulin-producing beta cells.

The technique has shown promise in mouse and monkey models of Type 1 diabetes, and it’s been licensed by gene therapy developer Genprex. But before it can be tested in people, some improvements need to be made, said lead researcher George Gittes, M.D., of the university’s McGowan Institute for Regenerative Medicine.

“In monkeys we’ve consistently reduced their insulin requirements by more than 50%, but we haven’t gotten them off insulin,” Gittes said in an interview. “So we’re fiddling with the way the two genes are made,” by improving the “capsid,” or coating of the AAV so it penetrates alpha cells and transforms them more efficiently, he explained. He hopes to be in discussions with the FDA about starting human trials by late 2022.

Type 2 diabetes, the far more prevalent form of the disease, is also a prime target for researchers working in gene therapy. Much of this work focuses on solving obesity, a major cause of Type 2 diabetes.

For example, a team at Washington University is focused on the gene FST, which makes the protein follistatin. Last year, the researchers reported that a one-time injection of the gene in mice blocked the muscle-modulating protein myostatin, which led to a buildup of muscle mass while also preventing obesity.

“The main takeaway was that doubling muscle mass, which this gene therapy did, basically put these mice into an incredibly healthy state,” said senior investigator Farshid Guilak, Ph.D., professor of orthopaedic surgery and director of research at Shriners Hospitals for Children – St. Louis.

Not only did the therapy prevent the obesity that should have resulted from the high-fat diet the rodents were fed, “all the inflammation that comes from being obese got eliminated. We even saw less arthritis,” he said in an interview.

As promising as all this research is, the prospect of moving gene therapy from the realm of rare diseases to such a common condition as obesity will raise challenging questions about who, exactly, should be treated with the technology, given that it can be prohibitively expensive, Guilak said.

“If someone is 10 or 20 pounds overweight, gene therapy just wouldn’t make sense,” he said. “But for someone who weighs 600 pounds and cannot lose weight, and needs to build muscle mass, this could be a lifesaver.”

Altering genetic variants to treat Alzheimer's

Another prevalent disease that could be a prime target for gene therapy is Alzheimer’s, which is estimated to affect more than 30 million people worldwide and is the leading cause of dementia. Variants of the gene APOE have been linked to the disease: People with two copies of APOE2 or one copy of each variant have a low risk of Alzheimer’s, while those with two copies of APOE4 face the highest risk.

Lexeo Therapeutics is developing a gene therapy that’s aimed at converting the APOE4/APOE4 brain to the lower-risk APOE4/APOE2 profile, CEO R. Nolan Townsend said in an interview.

The therapy, which delivers one APOE2 gene into the central nervous system, is being tested in a phase 1 safety study that should be completed by the end of this year, Townsend said.

The 15 patients in the study all have two copies of APOE4 and are showing symptoms of Alzheimer’s, Townsend said. In addition to tracking safety, the company will be measuring key Alzheimer’s biomarkers, including levels of the protein amyloid beta, which is known to form plaques in the brains of patients with the disease.

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Lexeo launched in 2018 with 18 gene therapy programs that were mostly developed at Weill Cornell Medicine, including the Alzheimer’s gene therapy. Other academic groups are targeting the disease, too, from different angles.

A team at the University of South Florida, for example, is developing a gene therapy that targets beta-arrestin-2, a protein that prevents the brain from clearing tau, another protein that has been implicated in Alzheimer’s.

Lexeo raised $85 million in a series A funding round in January—cash that will be essential as the company starts devising a plan to manufacture a gene therapy that could potentially reach a massive patient group.

“The good thing is the manufacturing technology in gene therapy is evolving positively, and we’re finding cell lines that have much higher yields than they did in the past,” Townsend said. “Manufacturing is the most significant strategic challenge we’re thinking through now, and I think we’ll be able to bring some of that new technology on board to address it.”