Meet the California Institute Pushing Stem Cell and Gene Therapy Research: Part 2

The California Institute for Regenerative Medicine (CIRM) is one of the largest dedicated funders of stem cell and gene therapy research in the world. In part 1 of our interview with Jon Thomas, President and CEO of CIRM, he explained the origins of the institute and how it has changed over time.

Now, he takes an in-depth look at the field of regenerative medicine and the key milestones, including the groundbreaking work of Shinya Yamanaka.

How has the remit of regenerative medicine changed over the years?
 

When the field first started, the focus was on embryonic stem cell research. Later, adult stem cell work was added, which had already been a separate research path for years. Then, there was a game-changer that fundamentally altered the field: the work of Shinya Yamanaka, which led to the production of induced pluripotent stem cells (iPSCs).

Around the mid-2000s, Yamanka was splitting his time between the University of Kyoto and Gladstone Institutes in San Francisco. We know the potential of embryonic stem cells, or pluripotent cells, but Yamanaka asked: could we somehow take an adult cell and reverse-engineer it back to that embryonic, pluripotent stage? It was an unusual question, but he pursued it – eventually discovering a combination of four proteins that, when applied together, could reverse-engineer adult cells back to a pluripotent state.

The discovery was revolutionary. For certain diseases where embryonic stem cells weren’t feasible, there was now a pathway to explore treatments. For incurable neurological disorders, for example, you could take an adult cell – perhaps a blood or skin cell – from a patient, reverse-engineer it to become a pluripotent stem cell, and then reprogram it to become neurons in a dish. So, for a Parkinson’s patient, you’d end up with neurons carrying the specific genotypes associated with Parkinson’s. You could then test potential drugs on those neurons in a high-throughput screening process. The work opened up the potential of personalized approaches to genetic disorders – and led to Yamanaka receiving the Nobel Prize in 2012.

The second major game changer is gene editing. Jennifer Doudna and her colleague Emmanuelle Marie Charpentier received the Nobel Prize for this work in record time because it was such a transformative approach. Since then, we’ve seen variations like base editing and prime editing, each of which are pushing the field forward. And we know there’s always a “next big thing” on the horizon, though we don’t know yet what it’ll be. Right now, we’re at a point where many research projects are moving into the clinical realm, which is pushing the field closer to commercialized therapies. It’s an incredibly exciting time, and the pace of discovery has accelerated so much that there’s real hope for treating diseases that were virtually untreatable 20 years ago.

What comes next for the field and what are the biggest challenges ahead?
 

One of the biggest challenges is manufacturing and producing cells in a way that ensures product homogeneity, quality control, and scalability. For treatments targeting prevalent diseases, the required manufacturing volumes will be substantial. This is something the industry hasn’t fully cracked yet, so new advances in cell manufacturing are crucial. It would also be great to see universal donor cells that can evade immune rejection and address the challenge of allogeneic approaches. Creating immune-evasive, universal cells would be a significant breakthrough.

We’re also likely to see more in vivo delivery of gene therapies. Currently, many of these treatments are done in vitro and then re-implanted, which creates scalability issues. If we can achieve in vivo delivery, it will fundamentally change the field. There are also ongoing improvements in the bioengineering of delivery devices. These devices aim to avoid immune rejection and prevent fibrotic effects that could interfere with their function. A lot of work is happening in this area, and I expect it will continue.

Looking further down the road, we may eventually reach a point where interventional genetics becomes routine. Imagine going to a clinic and having your full genome sequenced to identify the specific mutations causing your condition, and then receiving a personalized treatment… This vision is a bit farther out, but it’s where the field is heading.

Going back to the present and near-future, rare diseases will continue to be a key area of focus, but there is the question of how to get the biggest bang for your buck. One approach we’re exploring is a platform model using gene editing technology to target multiple genetic disorders through basket trials. In this model, a single gene editing approach is tested across various rare diseases at once. We’re working closely with the FDA to develop this approach with the goal of having regulatory buy-off going in.

How can we approach difficult conversations around costs?
 

While CIRM can’t directly control pricing as funders, we play a role in educating payers on the long-term economic value of cell and gene therapies. Even if the initial cost is high, one-time treatments can make more economic sense than lifelong care. In fact, a recent funding proposition that allocated an additional $5.5 billion to CIRM also includes a directive to focus on accessibility and affordability. We’ve now formed a working group of internal and external experts to ensure that any CIRM-funded therapies reaching commercialization will be accessible to all Californians.

We have also established a first-of-its-kind network of “Alpha Clinics.” These sites provide comprehensive support for clinical trials and have enrolled more than 2,000 patients across nine major research hubs, including Stanford, UC Davis, USC, Cedars-Sinai, and UC San Diego. This program has been a tremendous success, supporting both CIRM-funded trials and other cell and gene therapy trials. These clinics also collaborate on common IRBs and other frameworks to streamline and scale clinical processes. This network not only supports drug development, it enhances our role in educating the FDA, payers, and other stakeholders about these therapies.

What ongoing research projects are you excited about?
 

Few stem cell and gene therapy products have made it to commercialization, but we’ve seen a couple of sickle cell disease treatments approved for Vertex and Bluebird Bio, which are very exciting as proof of concept for their approach.

I’d also direct readers to check out Vertex’s work in type 1 diabetes. They’ve shared some recent updates where they’re advancing a fascinating approach that involves mature beta cells – the cells that produce insulin – developed in a lab. This concept was pioneered by Doug Melton. Essentially, they’ve been doing clinical trials where they transplant beta cells into patients, and the early results are really intriguing. Since they’re introducing foreign cells, there’s an immunosuppression element to prevent rejection. They recently presented findings at the American Diabetes Association: out of 12 patients in the trial, 11 have either reduced their daily insulin needs significantly or no longer need insulin at all. If this approach pans out, it would be groundbreaking.

Here in California, there are many interesting projects taking place. One project I’ll highlight is research from UCLA on severe combined immunodeficiency (SCID), specifically ADA-SCID. A researcher has developed a gene-editing technique to replace the mutated part of the hematopoietic stem cells responsible for the condition. The idea is to edit those cells and then return them to the bone marrow, where they’ll produce a normal blood supply with all the immunological components that people with SCID lack. They’ve had remarkable success in clinical trials and around 50 children have been functionally cured.

They are working towards a Biologics License Application, but the journey hasn’t been straightforward. They initially licensed the technology to Orchard Therapeutics, but Orchard ultimately shifted focus and didn’t pursue it. UCLA reacquired the rights, and we’re now funding this project as an academic effort once again. The lead principal investigator on this work is Don Kohn.

Of course, like with any research, there’s still a lot to see in terms of how things ultimately pan out. None of the projects we have funded have reached commercialization yet, but in the next three to five years, we firmly believe a number of our funded projects will reach the market. Because we fund research along the entire spectrum, we also support early-stage projects for diseases that are currently incurable. These projects might be laying the groundwork by identifying new biomarkers, for instance, which could fundamentally advance future treatments. We’re proud that at each stage, we’ve enabled scientists to make progress that will impact the field moving forward.

We’re extremely proud of our scientists. They represent an exceptional collection of talent here in California, and it’s a privilege to work with and support them.

Looking ahead, there are some incredible advances on the horizon. One area in which we expect to see growth is tissue therapies, where multiple cell types are combined into defined architectures that can be transplanted to regenerate tissue in a more “true to life” way. Of course, there’s always the chance for unexpected breakthroughs, like the Yamanaka or Doudna discoveries, that could redefine the field in ways we can’t anticipate.