Exonics to use CRISPR in an effort to treat majority of DMD boys

The early-stage CRISPR tech will be used to help up to 80% of DMD patients.

Exonics Therapeutics has won $5 million in seed funding toward its goal of using cutting-edge gene editing technology to help correct the majority of DMD mutations in young boys.  

The new CRISPR/Cas9 tech, which only began human testing in China last year, is yet to be tested in the clinic the U.S. (although this is on the cards for 2017), but has proven a major scientific draw for biotechs including Editas, CRISPR Therapeutics and Intellia, Caribou Biosciences, as well as academic work coming out of the University of Pennsylvania.

Much of the early work is focused on cancer (although it could be used against a host of diseases), and the idea behind the tech is to edit genes by leveraging an RNA guide molecule to enter in specific cells.

A protein called Cas9 then attaches to the DNA and essentially cuts it, all of which either gets rid of, completely removes or replaces a gene with a better strand of DNA. There has been much hype that this could help reverse of even cure a range of diseases, but it is all still very early-stage, and with questions needing to be resolved around potential safety issues, given how new the tech is.

The newly-launched Exonics, which comes with $5 million seed funding from CureDuchenne Ventures, will focus on using CRISPR in Duchenne muscular dystrophy (aka DMD), the most common severe form of childhood muscular dystrophy that hits young boys, with both their skeletal and heart muscles affected.

If untreated, they can lose their ability to walk at around 10 to 12 years old, and will typically die of their disease in their mid-20s due to heart failure. It affects around 15,000 boys in the U.S. and around 300,000 globally.

Until last year, the condition was predominately treated with a form of steroids, but in September, the FDA approved a new type of treatment for DMD called Exondys 51 (eteplirsen) from Sarepta.

Unlike steroids, this drug is specifically indicated for patients who have a mutation of the dystrophin gene (dystrophin is the key protein missing in boys with Duchenne) amenable to exon 51 skipping, which affects around 13% of the population with DMD.

Exonics, too, is looking to treat the mutations inherent in this disease, but is targeting a far larger patient population.  

Eric Olson, Ph.D., its scientific founder as well as professor and chairman of the Department of Molecular Biology at the University of Texas Southwestern Medical Center, has undertaken lab work showing the adeno-associated virus (AAV) can deliver a payload based on CRISPR/Cas9 technology that identifies and corrects exon mutations that prevent the production of dystrophin that helps stabilize and protect muscle fibers.

The company says that some early preclinical data “suggest that this approach has the potential to permanently treat up to 80% of children suffering from the disease,” with additional preclinical data expected next month.

The biotech says that this 80% could be “permanently treated,” and I asked Olson whether we were talking a cure. “Yes, we hope that a one-time treatment with a gene-editing therapy could provide a lifelong benefit to Duchenne patients, preventing further decline,” he explained. “Our research shows that a single systemic administration of gene editing components in adeno-associated virus has the potential to efficiently restore dystrophin expression throughout all skeletal muscles and the heart of mice with ‘humanized’ Duchenne mutations.”

He said that the company is currently targeting approaches to treat the most common mutations in Duchenne patients, including those mutations amenable to skipping exon 51 (targeted by Sarepta’s med).

“We are also working on therapies to skip exons 45, 53 and 44, which in addition to skipping exon 51, would allow treatment of 35% of known Duchenne mutations,” Olson explained.

“We anticipate development of sequences targeting up to 80% of the Duchenne population will follow once proof-of-concept has been demonstrated.”

In terms of timelines for getting into the clinic, Olson said: “The development timeline depends on many factors, including future preclinical studies that fully replicate the intended clinical delivery of the product, the safety profile to be confirmed in future toxicology studies and feedback from regulatory agencies. It’s important to generate robust and rigorous data to inform each next step as our program progresses.

“This is a novel area and we are committed to generating additional robust data that supports the development of a safe and efficacious therapy and advancing our Duchenne program thoughtfully to the clinic in a manner that allows most patients to benefit. We need to understand, to the extent feasible, potential risks prior to proceeding to the clinic and to receive critical input from regulatory agencies.”

While the initial focus is on DMD, Olson said that the biotech’s gene editing technology “has applicability across a wide-range of serious diseases.”

Jak Knowles, MD, Exonics’ president and interim CEO, and MD of CureDuchenne Ventures, tells FierceBiotech that while the biotech is early-stage, it is “building on an existing scientific program and not starting from scratch.”

Knowles explains: “One of the significant value-adds of the Exonics model is that we will leverage the expertise of the Olson lab to enable therapeutic development to proceed as quickly as possible. Our ability to move quickly is further enhanced by the drug development expertise of Exonics’ board and key expert consultants that have been engaged to help with regulatory planning. These features allow Exonics to be extremely capital-efficient and maximize the use of proceeds from our seed financing to de-risk and advance gene editing therapies for Duchenne and other neuromuscular diseases.”

On the corporate side, the $5 million in seed funding will only take things so far. Cristina Csimma, PharmD, MHP, Exonics’ executive chair and former (founding) CEO of Cydan, said: “The initial funding positions Exonics very well to meet critical milestones to advance the development program by further de-risking and creating value. We anticipate a Series A financing within the next 18 months.

“In the meantime, we will be opportunistic and engage in discussions, if and when appropriate, to help us expeditiously advance our program. We are open to working with other organizations, including venture capital and nonprofit foundations. There has been additional investor interest in the Exonics program already, and we have decided to take this focused, staged approach to the financing.”

Knowles will remain as interim CEO in the near-term, but I asked whether there will be a hunt for a full-time chief. Csimma said: “Right now, we are singularly focused on generating additional robust preclinical data that supports the development of a safe and efficacious therapy and advancing our Duchenne program. We will consider all staffing options that help us expeditiously advance the Exonics program, and we will make the best decision for the company at the appropriate time.”