Panel Explores the Rapidly Evolving Field of Genetic Medicines

By Allison Proffitt 

August 27, 2024 | In a panel discussion at last week’s Bioprocessing Summit, four leaders in genetic medicine shared insights into the rapidly evolving world of gene editing and its potential to revolutionize the treatment of complex diseases. Moderated by Ann Lee, Chief Technology Officer of Prime Medicines, the conversation highlighted the challenges and opportunities presented by advanced therapies such as CRISPR, base editing, prime editing, and epigenetic editing. 

Motivation for Gene Editing 

Manmohan Singh, CTO of Beam Therapeutics, emphasized the disruptive nature of gene editing technologies. His past experience had been in adjuvants, but gene editing drew him in. “The science is so compelling,” Singh said. “It’s almost disruptive technology and so cutting edge. That's what brought me to really take the leap of faith.” He described the rapid progress Beam has made, with four clinical programs underway, including two focused on ex vivo therapies for sickle cell disease and beta thalassemia. 

Similarly, E. Morrey Atkinson, EVP and Chief Technical Operations Officer of Vertex Pharmaceuticals, reflected on the company’s journey from small molecule development to genetic medicine. Vertex had primarily been a small molecule company, he said. “But the company decided to move into cell and gene therapy by acquiring a few different companies and partnering with CRISPR Therapeutics for cell therapy. So they needed someone to come in and help rethink the manufacturing strategy, and what technologies, capabilities, people and infrastructure we were going to need.” 

Innovative Approaches to Gene Editing 

Together the panelists gave what amounted to a “review article” on the history of gene editing technologies, joked Heidi Zhang, EVP and head of technical operations at Tune Therapeutics. Atkinson explained Vertex’s use of traditional CRISPR—first developed by Jennifer Doudna and Emmanuelle Charpentier in 2012—where hematopoietic stem cells are edited outside the body to treat diseases like sickle cell. “We remove the patient’s cells. We separate out the hematopoietic stem cells—the CD34s—and then we gene edit them by adding standard enzyme and guide RNA to edit at a locus that activates the fetal hemoglobin gene,” he said, and sends the edited cells back to the patient. “That sounds real easy. As everyone knows who does cell therapy, it’s really tough.”   

In contrast, Singh highlighted Beam’s work in base editing, a newer CRISPR technology developed by David Liu in 2016. Base editing doesn’t cause double-stranded breaks in DNA, Singh explained. It’s faster and allows for more precise point mutations. “You have the ability with base editing to multiplex edit. You can use and edit single point mutations at more than one site, both ex vivo and in vivo as well.” These are “one and done, curative therapies,” Singh said, adding that Beam has seen remarkable speed in taking these technologies from the lab to the clinic.  

Ann Lee discussed Prime Medicines’ work with prime editing, a next generation gene editing technology also developed in David Liu’s lab. The approach uses the same NICcase CAS enzyme, but instead of deaminase, prime editing uses a reverse transcriptase and a “very, very unique” guide, Lee said. The approach makes a single strand break in the 3’ side. “You can correct a lot of different size base pairs, and that’s part of its versatility,” Lee said. “You end up getting gene correction because the 3’ has preferential incorporation.”  

Finally Heidi Zhang, of Tune Therapeutics, introduced the concept of epigenetic editing, a different approach that involves tuning gene expression using de-activated CAS without cutting DNA to precisely target a gene of interest. “We can deactivate a protein, or we can silence protein expression,” Zhang said. “We can tune the protein expression to a certain given level… able to hone into the therapeutic window effectively.” While the technical challenges of epigenetic editing are very similar to the other types of gene editing, she noted, “the biology is so fascinatingly, fundamentally different.”  

Manufacturing and Regulatory Hurdles 

In common the technologies share Chemistry, Manufacturing, and Controls (CMC) concerns. All panelists agreed that the complexity of gene editing therapies creates unique hurdles for scaling production and ensuring regulatory compliance. 

Atkinson shared a particularly difficult challenge Vertex faced during the approval process for its gene therapy, CASGEVY. “We have really strict guidelines, particularly in the US, on particle control strategies and the presence of particles,” he said. “FDA is very strict about that. And so that was the thing that caught us most by surprise. We had to come up with a very comprehensive particle control strategy at a very, very late date to make sure that we met the regulatory expectations… That was super tough”  

Singh underscored the importance of working closely with regulators to demonstrate the efficacy and safety of platform technologies like base editing. Regulators need to be convinced that a platform approach works and can be applied even with product-specific guides, he said. “Changing the guide itself, you still have a very solid control strategy for the process,” he said.  

Lee agreed. “The guide is still relatively similar,” between products, she said. “I’m hoping that stability data, design space data—a lot of that is going to be the same, they’re going to let us not actually have to generate it. There’s no sense to generating redundant information. That’s, I think, the vision. We just all have to work together to navigate and influence our regulators.”  

The Future of Genetic Medicines 

Looking forward, the panelists expressed optimism about the future of genetic medicines while acknowledging the significant challenges that lie ahead. Zhang emphasized the potential of automation to streamline production processes and reduce costs, while Singh pointed to the growing role of artificial intelligence in optimizing drug delivery systems. 

However, all agreed that developing talent and fostering a collaborative work environment will be key to sustaining innovation, though Zhang noted that innovation from academia may present unique challenges.  

“People are the most valuable asset to any organization,” Zhang said. “Because the science is so new, leaders that really come into the [genetic medicine] start-up space tend to be academic individuals [with] very little prior industry experience to lean back on. It’s a different type of workforce with different sets of expectations,” she noted. Coming from the “publish or perish” world of academia, these researchers have a hard time relinquishing responsibilities to people they don’t know well or trust. But Zhang—and Tune—have seen significant growth here. “We’ve seen personal growth in a lot of our scientists in the earlier days of Tune. I’m so proud of them!”  

As the discussion concluded, the panelists shared advice for the next generation of biopharmaceutical professionals. Atkinson encouraged young scientists to be proactive in solving problems. “Don’t run from something,” he advised. “Run to something—run to the thing that excites you, where you think you can make a difference.” Singh added, “Be curious and be open to making mistakes. The best learnings will always come from failures… never be afraid to make more mistakes.” 

Zhang encouraged early career scientists to choose genetic medicine. “Honestly, biology is fascinating and we’re just at the beginning of it!” she said. The panel made it clear that while the road ahead for genetic medicines is complex, the potential to transform biotherapeutics is undeniable. As Lee aptly put it, “This is the kind of thing that’s going to really make a big difference in the future… All of us want to stay curious and learn.”