After spending over seven years at Sarepta Therapeutics working towards curing Duchenne muscular dystrophy (DMD) and other rare diseases, Bo Cumbo took the helm at a startup called AavantiBio to try to do something never done before—to target both the brain and the heart simultaneously with gene therapy.
Now, this wasn’t simply an exercise in targeting multiple organs at once; Cumbo’s idea was rooted in targeting the complex manifestations of Friedreich’s ataxia. Though most commonly known for progressive neurodegeneration affecting the cerebellum, deteriorating the brain’s connection and control of muscles and, ultimately, movement, the biggest threat to mortality for Friedreich’s ataxia patients is heart failure caused by a unique cardiomyopathy.
The way in which Cumbo envisioned doing this at AavantiBio was via a dual-route administration of gene therapies to avoid overwhelming the body with systemic administration. However, the fledgling company, established in 2017, encountered a problem during its preclinical trials in non-human primates (NHPs). No matter how much drug was given, it never got to both the cerebellum and the heart in a way that Cumbo has hoped.
“We had dosed several NHPs, and we realized that no matter how much you push the drug, whether it’s intravenously (IV), intrathecally (IT), or even dual-route administration—so IV and IT—you weren’t really getting to the cerebellum,” Cumbo told Inside Precision Medicine. “If you tried, you were going to cause toxicity.”
Around this time, the world was hit with the COVID-19 pandemic, and financial pressures led to a merger between AavantiBio and a company called Solid Biosciences, which was singularly focused on DMD and going through its own struggles trying to go toe-to-toe with Cumbo’s old employer, Sarepta Therapeutics. Solid is the English translation of Eytani, the Hebrew name of Solid’s co-founders’ Ilan and Annie Ganot’s son, who was diagnosed with DMD in 2012.
After the merger closed in December 2022, Cumbo took on the role of CEO and president at Solid Biosciences and has since rebuilt the entire management team, including Gabriel Brooks, MD, a cardiologist at Pfizer Therapeutics, who is chief medical officer and has transformed the company into a leading precision genetic medicine company. The company has since advanced its lead program in DMD, SGT-003, a next-generation adeno-associated virus (AAV)-mediated gene transfer therapy that contains an engineered, shortened version of the dystrophin gene (microdystrophin).
Right behind it is SGT-212, Solid’s program for Friedreich’s ataxia, which, using a new dual route of administration approach, seems to have broken through the wall Cumbo previously encountered while at AavantiBio and, in animal models, was able to deliver the gene therapy to both the brain and heart. This week, the FDA approved Solid Bioscience’s IND for direct delivery of the AAV-based gene therapy to the cerebellum and heart to potentially treat the neurologic and systemic clinical manifestations of Friedreich’s ataxia and address the full spectrum of disease progression.
“I’m very hopeful we can solve the delivery issue and help Friedreich’s ataxia patients right where their disease is,” said Cumbo. “So, if you’re 35 years of age, just with the CNS manifestations of the disease, I’m hoping SGT-212 will be a drug for you. If you’re 20 years of age, and you have CNS manifestations and are starting to have severe or worsening cardiac manifestations, I’m hopeful we will have a drug for you. And if you’re two years of age, just diagnosed, and you don’t know what your journey is going to be—it’s unknown—I’m hopeful that we will have a drug for you.”
The delivery breakthrough
The hurdle for SGT-212 was the inability to get the drug to infuse the cerebellum fully. According to Brooks, when using direct injection with a needle in NHPs, Solid Biosciences researchers would only observe minimal transduction of SGT-212.
“We have concluded that intravenous or intraventricular dosing would be unable to penetrate the deeper structures in the cerebellum, irrespective of vector tropism, without pushing the dose so high that it would cause systemic toxicity,” said Brooks. “Additionally, traditional intraparenchymal delivery techniques lead to vector transduction only at the immediate site of vector deposition, or around the needle track, due to reflux and poor penetrance of brain parenchyma, leading to a steep concentration gradient and only a very modest distribution of transduced tissue. This is why we have specifically chosen highly targeted IDN infusion using cutting-edge confection-enhanced delivery, which will deliver our therapy directly to the targeted dentate nuclei.”
The dentate nucleus is the largest of the deep cerebellar nuclei, with dendritic length of around 10 millimeters, making it a relatively large structure within the brain. By using an MRI-guided, convection-enhanced delivery (CED) that allows for a predictable, homogenous distribution, unlike diffusive therapies limited by concentration gradients, Brooks said SGT-212 is expected to sufficiently infuse into the dentate nucleus and transduce neurons critical for voluntary movement to address ataxia and dysarthria along with bulbar functions such as swallowing.
“I know other companies are going to try to do it different ways, either from a cardiac-only standpoint or from a neurotropic capsid standpoint, trying to solve it all with one round of delivery, and it might work,” said Cumbo. “But we’ve done so much preclinical work and feel confident that you have to get into and coat the dentate nuclei. There really are no shortcuts.”
One of the more significant challenges for targeted drug delivery in humans is directly measuring how much of the drug got to the intended site. A major upside of Solid’s delivery technique to the brain is that SGT-212 is being paired with gadolinium, a rare earth metal used as a contrast agent in MRI scans, to visualize the distribution of the drug.
“The gadolinium enhancement demonstrates the exact distribution of the drug, so by the end of the treatment procedure, we will know, to the minute, ‘Did we deliver the drug to where it needed to go?’” said Brooks. “When we’re sharing our initial safety and tolerability data, and initial cardiac transduction and expression, we will be able to say we had profound real-time imaging to provide proof that the target organ, the dentate nucleus of the cerebellum, received delivery of the drug. Since the vector infusion will include an MRI imaging agent, we will know exactly where the virus was injected. We fully expect that by the end of the injection process, we will have imaging proof that the target organ, the dentate nucleus of the cerebellum, was completely treated by the drug.”
Racing for Friedreich’s ataxia gene therapy approval
Solid expects to initiate the first-in-human, open-label Phase Ib clinical trial of SGT-212 in the second half of 2025. The study will enroll non-ambulatory and ambulatory adult patients living with FA across up to three cohorts and evaluate the safety and tolerability of systemic and bilateral dentate nuclei administration of SGT-212. Participants in the trial will be followed out to five years after receiving SGT-212.
Solid’s dual-route administration delivery approach gives their Friedreich’s Ataxia program an edge, but there are other horses in the race, notably Voyager Therapeutics. In collaboration with Neurocrine Biosciences, Voyager is currently developing a gene therapy for Friedreich’s ataxia using its TRACER capsid discovery platform, which identified a new AAV capsid that can penetrate the blood-brain barrier. According to data from February 2024, preclinical NHP studies using IV injection for the Voyager-Neurocrine FXN gene therapy achieved target FXN expression levels in the cerebellar dentate nucleus, sensory ganglia, and heart, with FXN levels similar to those present in control normal human brain tissue. So, Voyager and Neurocrine Biosciences, expected to file INDs for Friedreich’s Ataxia gene therapy program in 2025, aren’t far behind, breathing behind Solid Biosciences’s back.
