Gene Therapy Promising for Rare Syndrome

Jim Kling

April 23, 2021

A gene therapy strategy has produced impressive results in patients with Sanfilippo syndrome type A (mucopolysaccharidosis IIIA). Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.

The study was presented at the American Academy of Neurology's 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children's Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. "There's been nothing shown to change the cognitive pathway of the disease. This is the first time it's been seen as a treatment effect," Flanigan said during a follow-up Q&A session.

The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. "There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We've not seen signals of anything reminiscent of that, and we're at AAV-9 dosages that are quite similar to what's been used elsewhere in the field," said Flanigan.

The results have him optimistic about the therapy. "I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That's a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It's really gratifying to watch," said Flanigan.

The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. "Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome," said Johnson, who attended the session but was not involved in the research.

Toxicity could remain an issue, even in the absence of AAV-based safety concerns. "The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it's unclear what the upper limit of toxicity would be for adults," said Johnson.

Transpher a Study Results

Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.

Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.

The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. "More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients," said Flanigan.

The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.

The study was funded by Abeona Therapeutics. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Flanigan has received funding from and been a consultant for Avidity.

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