Fierce Biotech Summit: Gene editing execs reflect on promises and challenges as CRISPR celebrates 10-year anniversary

Ten years ago, a little-known Science paper authored by Jennifer Doudna, Ph.D., and Emmanuelle Charpentier, Ph.D., proposed using CRISPR/Cas9 for gene editing. As the first wave of gene-editing-based therapies post clinical data and head to the FDA, biopharma executives at the forefront of the burgeoning field highlighted the innovations and challenges before gene editing is ready for prime time.

Gene editing tools have been around for some time, but CRISPR “democratized” the field by eliminating the need to develop custom-engineered gene cutters for particular sites in the genome, Craig Mickanin, global head of the genomic sciences group at Novartis Institutes for Biomedical Research, said during a panel discussion at the inaugural Fierce Biotech Summit.

Pointing to newer gene editing technologies like base editing and prime editing, Mickanin argued that the recent acceleration of innovation in genome editing wouldn’t have been possible without making the tools more broadly available.

Now, some of the early efforts of turning CRISPR gene editing technology into viable therapies are coming to fruition. Vertex and partner CRISPR Therapeutics just announced their plan to file their CRISPR/Cas9-edited cell therapy exagamglogene autotemcel (exa-cel) for a rolling review at the FDA in sickle cell disease and beta thalassemia starting in November. If approved, exa-cel could be the first CRISPR-based therapy available.

Meanwhile, Intellia Therapeutics, after being the first to show that systemic infusion of CRISPR inside the human body could treat disease, recently reported more positive early data for its in vivo gene editing candidates for transthyretin amyloidosis (ATTR) and hereditary angioedema.

For Intellia’s candidates, the company is using a lipid nanoparticle to deliver CRISPR to cripple genes in the liver. “But we want to go well beyond that […] and what that involves is being able to deliver to other tissues,” Intellia’s chief medical officer David Lebwohl, M.D., said at the Fierce Biotech Summit.

As Tessera Therapeutics’ chief scientific officer Michael Holmes, Ph.D., sees it, advances in genetic materials’ delivery vehicles have really enabled the transformation of genome editing tools into actual therapeutics.

The entire gene therapy field took a serious hit in 1999 with the death of Jesse Gelsinger after he had received an experimental gene therapy for a rare X-linked genetic disease. The tragic case was believed to be caused by a hyperimmune response against the vector used to deliver the gene therapy.

Safer vectors have been developed since then, but safety questions around gene therapy persist. For gene editing technologies specifically, potential off-target editing is a well-known problem with even the best CRISPR system out there.

Off-target editing analyses were also a part of the FDA’s request list in a recent clinical hold on Beam Therapeutics’ phase 1-ready, base-edited CAR-T program for blood cancer. So, how safe is safe enough for a gene editing therapy to be tested in humans?

“For off-targets, there’s no one-size-fits-all rule for what’s appropriate to bring forward to the clinic,” Jason Gehrke, Ph.D., head of immunology at Beam, said during the Fierce Biotech event.  

For one thing, the acceptable benefit-risk balance is different among different diseases—the off-target risk profile of a CAR-T therapy for late-line cancer may not be appropriate for a stem cell therapy for sickle cell disease, Gehrke said.

And not all off-targets are equal. Intergenic off-targets have a completely different risk profile than an unintended edit that falls in a gene or an enhancer, he added.

“In the end, I think the teams who are developing these therapies need to work to minimize off-targets first,” Gehrke said. “And for those off-targets that they can’t get rid of, use preclinical assays and models to de-risk them to the best degree possible, and then come together to determine whether that particular risk profile is appropriate for the patients that they intend to treat.”

For now, most gene editing projects are focused on rare diseases and some blood or cancer indications with well-established genetic drivers. Those diseases have clear clinical endpoints and risk-benefit understanding to allow for a quick drug development path. Further, targeting them can help companies test out their technologies without layering on too many biological risks, Tessera’s Holmes said.

For example, ATTR drugs like Alnylam’s Onpattro that target TTR through RNA interference have proven successful. Intellia has shown its ATTR gene-editing candidate could knock out the TTR gene, leading to over 90% of reductions in the toxic buildup of the TTR protein. And a randomized clinical trial could compare the gene editing therapeutic with existing standard of care, Lebwohl said.

Mickanin also agreed that initially treating genetically defined diseases is a benefit-risk consideration for gene editing players. But there’s a “really strong interest and a willingness to take on a little bit of risk” to expand into more common diseases, Mickanin said.

But getting into more prevalent diseases could be much harder. Many conditions may be multifactorial, Mickanin said, meaning they are caused by several genetic factors. That requires both a better understanding of the basic biology of diseases but also more powerful gene editing tools.

“We are still learning about the human genome; we are still learning about the genetic underpinnings of disease,” Mickanin said. “As we learn more about this, it’s going to […] help us understand, what are the multifactorial, polygenic nature of diseases, which may open up some of these opportunities to go into more common diseases, coupled with the ability to potentially modify multiple genes simultaneously.”

Novel delivery tools might also help gene editing breach into common diseases with better safety, Mickanin said. Delivery capabilities that could take therapies to tissues that are currently difficult to reach could allow gene editing to make the next quantum leap, Beam’s Gehrke said.

“We want to be able to get to muscle, we want to get be able to get to the CNS; there are a lot of places that you can go,” Lebwohl said. Accessing different cells and tissues may also require various gene editing tools, he added. These include genetic scissors like Cas9, base editors and gene writers.

Ex vivo gene editing therapies like Vertex and CRISPR Therapeutics’ exa-cel, in which a cell is modified outside the body, may be a more popular approach for now, but Intellia has shown direct editing inside the body is possible. That in vivo method might be the way to go.

“I would predict one of the biggest breakthroughs is that we will be able to do all the types of editing that we want to do without having to take any cell out of the body,” Holmes said. “This will make [gene editing] more transformational, but also much more cost effective.”