MDA 2025: Experimental gene therapy boosts frataxin in primates
CAP-004 seen to safely increase brain, heart levels of deficient protein
CAP-004, Capsida Biotherapeutics’ experimental gene therapy for Friedreich’s ataxia (FA), safely delivered its genetic cargo to key disease-related tissues in nonhuman primates, new research shows.
Specifically, that cargo was delivered to the heart, sensory nerves, and the central nervous system, or CNS, which comprises the brain and spinal cord.
In the brain and heart, the therapy was found to boost levels of frataxin — the protein that’s deficient in FA — to a degree expected to be therapeutically relevant in FA patients, according to company data.
In a talk at the Muscular Dystrophy Association’s 2025 MDA Clinical & Scientific Conference, held last week in Dallas and virtually, Ryan Kast, PhD, a senior scientist at Capsida, said these data position CAP-004 as a “best-in-class” therapy with the potential to address cardiac, CNS, and sensory manifestations of FA.
A slide accompanying Kast’s talk noted that a “single [intravenous, or into-the-vein] administration of CAP-004 in [primates] demonstrates potential for complete correction across all CNS target tissues.”
The presentation was titled “CAP-004: Systemic AAV Gene Therapy with Engineered Capsids for Treatment of CNS and Cardiac Symptoms in Friedreich’s Ataxia.”
CAP-004 designed to deliver functional version of FXN
FA is caused by mutations in the FXN gene that lead to a loss of frataxin, a protein important for energy production within cellular organelles called mitochondria. Nerves and muscles, which have high energy demands, are particularly vulnerable to this frataxin loss.
Energy deficiencies and related damage in these cell types drive FA symptoms, which include balance and coordination problems, muscle weakness, sensory impairments, and heart problems.
A one-time gene therapy, CAP-004 is designed to deliver a functional version of FXN, thereby enabling cells to continuously make their own frataxin. This is expected to ease FA symptoms and slow disease progression. The treatment particularly seeks to target tissues affected in FA, including the CNS, sensory nerve cells outside the CNS, and heart cells.
Gene therapies are commonly packaged up into a capsid — the protein shell of a virus — to help them be taken up by their target cells. Adeno-associated viruses, or AAVs, are often used for this purpose.
However, first-generation AAV capsids have a limited ability to cross over the selective blood-brain barrier (BBB) that protects the CNS, limiting their therapeutic efficacy in the brain and spinal cord when given via an intravenous infusion.
CAP-004 uses a specially engineered, next-generation AAV capsid with an enhanced ability to cross over the BBB and access the CNS. It’s also expected to have less liver toxicity and fewer off-target safety concerns.
Frataxin levels in brain 8 times higher after experimental gene therapy
The potential benefits of this experimental gene therapy were demonstrated in the data from non-human primate studies that Kast presented. Per these data, a single dose of CAP-004 led to higher RNA expression — reflective of greater gene activity — in the brain, spinal cord, sensory nerve cells, and retina relative to a commonly used capsid called AAV9. The retina is the back part of the eye that sends signals to the brain.
Importantly, CAP-004 was associated with lower RNA expression in the liver, demonstrating its potential ability to avoid liver toxicity.
CAP-004 delivered its genetic cargo to, or transduced, about 80% of cells in CNS tissues — including areas of the brain and spinal cord — with a single administration.
In addition to producing this protein in the right … tissue structures … we want to make sure that in the cells that it’s produced that it’s actually functional.
Moreover, the FXN gene was delivered to about 30% of the heart’s left ventricle, a transduction efficiency that’s expected to be therapeutically meaningful and which is in line with the performance of other AAV capsids, according to Kast.
The scientist noted, however, that, “in addition to producing this protein in the right … tissue structures … we want to make sure that in the cells that it’s produced that it’s actually functional.”
Frataxin is initially made as a protein precursor that’s eventually transformed into a mature, functional version within mitochondria. Analyses of brain and heart tissue from primates treated with CAP-004 showed that the majority of frataxin present in these tissues was the mature form.
The gene therapy was associated with frataxin protein levels more than eight times higher than was seen in untreated controls in the brain’s motor cortex. It also was about 1.7 times higher in the hearts of the treated animals.
These values exceed what’s expected to be efficacious in people with FA, according to Kast. Across studies, CAP-004 was also well tolerated without specific safety concerns.
Kast noted that ongoing preclinical studies, aimed at moving the treatment toward clinical testing, will investigate the long-term durability and safety CAP-004.
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