In vivo gene editing grabs the spotlight after Intellia triumph, but challenges loom

In early September, 15-year-old gene therapy developer Precision BioSciences devoted its entire two-hour R&D presentation to products in its pipeline that involve in vivo gene editing—therapies designed to be injected directly into patients to correct genetic diseases.

Co-founder and Chief Scientific Officer Derek Jantz, Ph.D., kicked off the event with a deep dive into the in vivo therapies Precision is developing to address four different diseases, and then he took questions from Wall Street analysts. Much of Jantz’s presentation, and several of the questions that followed, focused on whether the company’s technology could adequately ameliorate the risk of off-target gene editing—inadvertent changes to patients’ DNA that could cause dangerous side effects.

The event, therefore, was a perfect snapshot of the sentiments surrounding gene therapy right now.

On the one hand, investors are enthusiastic about the next generation of gene-focused treatments, most notably in vivo gene editing. That field got a major boost in June when Intellia Therapeutics’ stock skyrocketed on positive first-in-human data for its in vivo candidate, NTLA-2001, designed to treat patients with transthyretin amyloidosis.

But all of these companies are advancing their next-generation gene therapies toward the clinic at a time when the first generation is coming under intense scrutiny.

On Sept. 3, an FDA advisory committee spent two days discussing safety concerns surrounding currently marketed gene therapies, including Novartis’ Zolgensma to treat spinal muscular atrophy and Spark Therapeutics’ Luxturna used to treat an inherited eye disease. The emergence of liver toxicity, neuron loss and other side effects has the FDA reconsidering everything from the preclinical models used to assess the safety of gene therapies to screening methods that might select the patients least likely to suffer adverse events.

Related: FDA committee takes on complex gene therapy safety questions with Novartis' Zolgensma providing lessons learned

Much of the discussion around the next generation of gene therapies centers on how they’re delivered to the body. The treatment that launched in vivo gene editing into the spotlight, Intellia’s NTLA-2001, uses a lipid nanoparticle (LNP) to precisely knock out a disease-causing gene in the liver with the gene-editing technology CRISPR/Cas9. Other in vivo contenders are employing a wide range of delivery vehicles and editing technologies, in hopes of moving beyond what Precision’s Jantz refers to as the “low-hanging fruit.”

“You can use any gene-editing technology to knock genes out in the liver. But there is a limited number of diseases one can treat that way,” Jantz said in an interview with Fierce Biotech. “To treat the vast majority of genetic diseases, you have to deliver your technology to some other organ.”

Precision’s core technology, called ARCUS, uses sequence-specific enzymes called nucleases to cut DNA and then insert, remove or fix genes. It’s designed not only to be able to penetrate tissues outside of the liver but also to be more compact than other editing technologies, Jantz said. Those attributes are key to one of Precision’s lead programs, a Duchenne muscular dystrophy (DMD) treatment that will be delivered to muscle.

The treatment cuts out 10 coding portions, or exons, of the gene that makes dystrophin, a protein key to muscle function. Most of the mutations that cause DMD occur within that 10-exon stretch, Jantz explained. “We’ve shown we can use ARCUS to chop out the entire region, which creates a slightly truncated but functional form of the dystrophin gene,” he said.

Precision developed ARCUS in a way that allows it to tag the portions of the genome it cuts, leaving behind a signature that its scientists can use to detect off-target edits. They can then use that information to fine-tune the enzymes and lower the risk of off-target editing, Jantz said.

Precision is working on the DMD program and two others with Eli Lilly, which inked a $135 million deal with the company last November. Safety was a major factor in Lilly’s decision to partner with Precision, said Ruth Gimeno, Ph.D., vice president of diabetes and metabolic research at Lilly, in a video shown at Precision’s R&D day. “We … need a high degree of specificity, because safety is always on our minds,” she said.

Related: Lilly, Precision Biosciences team up on Duchenne gene therapy in $135M deal  

In all the hoopla surrounding Intellia’s in vivo gene editing results, it’s easy to forget that it wasn’t the first company to report data from a clinical trial of the new technology. In 2019, Sangamo Therapeutics posted phase 1/2 data from a trial of SB-913, which used the company’s zinc finger technology to repair a faulty gene that causes Mucopolysaccharidosis type II (MPS II), which is also called Hunter syndrome.

Sangamo’s zinc fingers are engineered to bind to specific DNA sequences and insert therapeutic nucleases or transcription factors into them. In the case of SB-913, the technology cut the DNA of certain liver cells and deposited a functional copy of the IDS gene, which made an enzyme that patients with Hunter syndrome lack.

Problem was, IDS levels rose in only one of the six patients enrolled in the trial, and levels of the enzyme started falling after six weeks. Sangamo CEO Sandy Macrae explained in an interview that the problem was traced not to the technology, but to the delivery vehicle, which in the case of SB-913 was an adenovirus vector (AAV). “Our analysis of it is that we didn’t get enough of the [gene editing] components in every cell,” he said.

So Sangamo went back to the drawing board and is now investigating several alternative delivery techniques, including lipid nanoparticles and capsids that may be able to transport gene-editing technology via IV injection. It has formed several partnerships to advance the research, including one with Takeda focused on Huntington’s disease and another with Pfizer to work on amyotrophic lateral sclerosis and frontotemporal degeneration.

Beam Therapeutics, which is working on in vivo gene editing approaches to treating liver and eye diseases, is also increasing its stable of delivery technologies. In February, it paid $120 million to acquire Georgia tech spinout GuideTx and its lipid nanoparticle technology.

Guide created DNA “barcodes” for several formulations of LNPs, which will allow Beam’s scientists to identify delivery vehicles that are optimized to target specific organs and tissues. “We believe LNP has the opportunity to become a much broader delivery technology across the body than what was originally anticipated,” said Pino Giuseppe Ciaramella, Ph.D., chief scientific officer of Beam, in an interview.

The quest for better vectors to deliver in vivo gene editing has generated excitement for some startups working in that area, including Ensoma, which launched in February with $70 million in venture capital to develop its Engenious vectors. They’re adenoviruses that have been cleared of all their viral DNA and RNA, leaving room for therapeutic gene-editing material that might be too big to fit into other vectors.

What’s more, “they’re engineered to be very specific to hematopoietic stem cells, so they won’t get into the liver and produce off-target effects,” said Paula Soteropoulos, executive chairman of Ensoma, in an interview.

Sangamo’s Macrae predicts that several in vivo editing approaches will ultimately work, benefiting patients with a wide range of diseases—provided the delivery challenges can be overcome, safely of course.

“In vivo gene editing was always going to happen,” he said. “What Intellia’s announcement proved was that LNP could deliver CRISPR without damaging the liver. In five to 10 years, we won’t hear about what form of editing it is. It’s all going to be about the delivery and getting enough of the technology into the cell.”