Gene therapies — after a tragedy kicked them back to the lab some two decades ago — are beginning to come into their own, making possible work in gene-targeted and combination treatments for neuromuscular diseases once unimaginable.
But many challenges — from the likelihood of no “one and done” gene therapy for diseases like muscular dystrophy, Pompe or Friedreich’s ataxia, to the sheer amount of vector needed for both systemwide and central nervous system treatment — remain, especially for rare neuromuscular ills, said Sharon Hesterlee, PhD, an executive vice president and chief research officer for the Muscular Dystrophy Association.
Jesse Gelsinger’s death in a gene therapy trial in September 1999 “really set the whole field back for a long time,” Hesterlee said in a wide-ranging phone interview with BioNews Services, the parent company of this website.
But the MDA “continued to invest … through that whole dry period, with the thought that this is going to work, we just have to figure out how.”
Hesterlee has a more than 20-year career in the pharmaceutical and biotech industries as well as nonprofits (including with the MDA, where she worked in drug translation and venture philanthropy from 1998 to 2009).
She welcomes gene therapy’s return, and some sense of accomplishment for the more than $1 billion the group has invested in neuromuscular disease research since its 1950 founding.
“Now we’re seeing the maturation of that [gene] technology, a much better understanding of the issues, and we’re starting to see successes,” she said.
She, like others, points to the U.S. approval of a first gene therapy in a neuromuscular disease — Zolgensma, by Novartis, for spinal muscular atrophy (SMA) — as an initial breakthrough and a sign of what might yet come.
Translating that success to other patients, however, will take time.
Two big challenges, but glimmers of hope
Two broad challenges exist for gene therapies in neuromuscular ills, especially rare ones, Hesterlee said, with numerous mini-hurdles within those categories.
One is getting the therapy to all affected muscles and organs and, along with that, being able to produce the huge amounts of viral vector required to transport it.
As one recent study of work into a Pompe gene therapy, by scientists that include Barry Byrne and Manuela Corti at the University of Florida (UF), noted: the vector amounts necessary “exceed” current production techniques on a scale that “would not be suitable to support” either Phase 3 clinical trials or regulatory approval requests.
The other is the real likelihood that such treatments would have to be given again over a person’s lifetime, which means getting around resistance raised by the immune system. An immune response to a gene therapy comes in the form of antibodies against whatever virus carries the “healthy gene” to cells as a transport vector, even when that virus is re-engineered to be harmless.
“I think we know we’re going to have to treat people again, and right now what we’ve done is immunize them against the vector,” she said. “They’re developing really high antibodies after treatment, so you can’t use the same vector.
“I think that’s going to be a big, big challenge: How do we deal with people that have pre-existing antibodies, and then how do we deal with redosing?”
The challenge of knowing whether Zolgensma is truly a one-time SMA treatment remains. A gene therapy is likely to be much more stable in the central nervous system (CNS, comprising the brain and spinal cord) than in muscle, Hesterlee said, but only time will definitively tell.
“People speculate ‘one and done‘ [but] we know that might not be the case,” she said. “We just don’t have enough long-term data to really understand how long this lasts in muscle, how long this lasts in the CNS.”
Scientists are meeting these challenges head-on. Hesterlee mentioned a Phase 1 trial (NCT02240407), underway by Byrne and others at UF, that is redosing people with late-onset Pompe disease, using an immuno-suppression regimen described in a recent study.
And, happily, cooperation across private interests and nonprofit patient groups like the MDA is coming to the fore.
Examples here include a first multi-drug, or platform, clinical trial for a neuromuscular disease like amyotrophic lateral sclerosis — the Healey ALS Platform Trial — and growth in collecting and sharing comprehensive patient data, like the MOVR registry the MDA is establishing.
“It really does make sense that you want to bring as many resources together as possible in rare disease spaces. You can’t duplicate resources,” Hesterlee said.
Meanwhile, “less rivalry” is evident across companies, institutions and associations, and that’s a huge leap, she said.
“People are starting to share the datasets they used to horde. I think all of this … bodes well for the future.”
Upcoming for Duchenne, other dystrophies
Duchenne research in recent years has been a mix of “some remarkable successes, and some really disappointing failures,” Hesterlee said.
Leading those successes are the two approved exon-skipping treatments by Sarepta Therapeutics that work to restore dystrophin expression in people with Duchenne. The therapies allow a shorter but functional dystrophin protein — essential for muscle health — to be produced.
Duchenne is caused by the loss of dystrophin due to mutations in different exons (tiny bits of DNA containing information needed to make proteins) in the DMD gene, the largest of all human genes.
These treatments, which leapt the field beyond corticosteroids as therapy, are Exondys 51 (eteplirsen) for patients amenable to exon 51 skipping in that disease-causing gene, and Vyondys 53 (golodirsen) for those amenable to exon 53 skipping.
Other promising work spotted by Hesterlee includes:
- Casimersen, a potential exon 45 skipping treatment by Sarepta, now in the Phase 3 ESSENCE clinical trial (NCT02500381), which is enrolling eligible patients (boys ages 7 to 13) at sites outside the U.S., including across Europe
- Edasalonexent, an oral, small molecule therapy by Catabasis Pharmaceuticals, now in the Phase 3 PolarisDMD trial (NCT03703882) in boys with Duchenne, ages 4 to 7. It’s designed to prevent the breakdown of muscle fibers, and as such works as a kind of steroid-sparring therapy, Hesterlee said.
- Vamorolone, by ReveraGen Biopharma, another such therapy now in a two-year extension study, VBP15-LTE (NCT03038399), in 45 Duchenne children
- Raxone (idebenone), by Santhera Pharmaceuticals, being tested as a breathing aid for Duchenne patients in a Phase 3 trial (NCT02814019, still enrolling) called SIDEROS, and its open-label extension study (NCT03603288) called SIDEROS-E, which also is recruiting participants
Disappointments, Hesterlee said, are led by a failed clinical trial for suvodirsen, an exon 51 skipping treatment by Wave Life Sciences with a potentially more effective approach that failed to increase dystrophin levels. Its development was discontinued in late 2019. Also included is work by Pfizer into domagrozumab, a monoclonal antibody to block myostatin, a protein that limits muscle growth — essential for healthy people, but detrimental to those with muscle wasting diseases. Investigation into domagrozumab was terminated in August 2018.
“Something failed to translate” from animal disease models, Hesterlee said. But “if we can learn from the failures … those efforts will still be useful gains for the field.”
Gene therapies for Duchenne
She and the MDA are closely watching, and often financially supporting, work in gene-targeted treatments, especially the mini-dystrophin gene therapies now in clinical studies by Pfizer (PF-06939926), and Solid Biosciences (SGT-001).
“The mini-dystophins that have been developed are good, but they’re not likely to be as good as the whole linked dystrophin … because there you’re taking off a piece of the gene and putting it back together,” Hesterlee said.
“Carefully optimized” gene therapies, in contrast, “have the ability to completely build from scratch these mini-dystrophins,” she said.
Pfizer’s open-label Phase 1 trial (NCT03362502) is evaluating the safety, tolerability, and early effectiveness of a single dose of PF-06939926, at two dose levels, in up to 15 Duchenne boys, ages 4 to 12 and able to walk. That trial is still enrolling at sites in California, North Carolina, and Utah.
Solid Biosciences’ Phase 1/2 study of SGT-001, called IGNITE DMD (NCT03368742), was placed on a second clinical hold in November 2019 after a 7-year-old boy developed serious side effects to the adeno-associated viral (AAV) vector-delivered therapy. A first hold on the therapy, in March 2018, was lifted three months later, after Solid changed the study’s design.
The company is now working with the U.S. Food and Drug Administration (FDA), and restructuring internally, to allow work on SGT-001 to continue. The therapy has shown a promising microdystrophin response, without harm, in two other boys treated at the highest dose given in the trial.
“I think we will see more and more of these gene-targeted therapies, maybe even including gene editing [like CRISPR-Cas9] as that technology starts to mature,” Hesterlee said.
The MDA, which awarded $16.8 million in direct research grants in 2019 as part of a total $66 million multi-year funding commitment, helped to support the development of each of these three potential therapies. Moreover, the association anticipates giving out about $18 million in new direct grants in 2020.
Treating a gene as large as DMD, however, has “always been a challenge for Duchenne,” Hesterlee said, largely because of “the sheer amount of vector that’s required to treat a muscle disease systemically.”
That’s true for all muscular dystrophies — and most of the 40 distinct, and often rare, neuromuscular diseases the MDA represents.
A recent report funded by the MDA found that “upwards of 80 in every 100,000 individuals, or more than 250,000” people in the U.S. have a neuromuscular disease — putting it beyond what the country defines as a rare or orphan disease.
“It is almost overwhelming to think about generating [vector] enough to treat all … the people who are alive right now,” should any one gene therapy prove its worth, Hesterlee said.
And for other dystrophies
Potential gene therapies for limb-girdle muscular dystrophy also are advancing, particularly the calpain-3 program for LGMD type 2A, and SRP-9003 for LGMD type 2E, both by Sarepta. SRP-9003 is currently being tested in a Phase 1/2 trial (NCT03652259).
Likewise, AskBio — for whom Hesterlee worked, along with Pfizer — is moving forward on a gene therapy for LGMD, particularly type 2i, while Santhera is working on a treatment for LAMA2 MD, a type of congenital muscular dystrophy.
Other treatments sparking interest, whether they’ll be seen to work as intended or not, include “a sleeper-thing” of a molecule called ribitol (BBP-418). That therapy, also for LGMD type 2i, is “almost like a food additive … a substate for the enzyme that’s mutated in that disease,” Hesterlee said. Early work in animal models has been “very good,” she said.
Combinations are ‘the future’
But gene therapies for muscular dystrophies will likely never be “one and done,” Hesterlee said. That’s because the viral vector used — some form of an AAV — goes into mature muscle cells rather than dividing cells.
“And if you add muscle mass,” as you age and grow, “you’re not making more copies of that gene that you brought in,” she said. “It sits outside the chromosome, so it will eventually get diluted … I think we know we’re going to have to treat people again.”
That once again raises the issue of overcoming antibodies against a vector, and allowing for redosing.
Gene therapies, or gene-targeted therapies, also lend themselves to combination treatments. That’s what is happening in SMA with Zolgensma, and another approved treatment that works on a different gene — specifically, Spinraza, by Biogen. It’s also occurring with a similar oral treatment now under FDA review, namely risdiplam, by Roche and Genentech.
Such small molecule approaches address “downstream things” from the mutated gene the therapy is targeting.
“In theory at least, you could predict synergestic results,” Hesterlee said. “And as more [of these small molecules] get approved, I think combining them is the next logical step.”
“And it will happen, whether they’re tested in clinical trials or not,” she added.