New gene therapy may correct nerve and heart problems in FA: Study
Experimental treatment shown to boost frataxin in animal models
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Researchers have developed a new type of gene therapy that, according to the findings of a new study in animal models, may correct both nerve and heart problems in people with Friedreich’s ataxia (FA).
The one-time treatment, administered via a spinal tap, was designed to simultaneously target the heart and the nervous system. In mouse models, it boosted the production of frataxin, the protein that’s deficient in FA, to levels associated with a near-complete rescue of disease features.
Additionally, in primate models, increases in frataxin levels as a result of the new gene therapy did not exceed a threshold that’s been associated with toxicity.
While the therapy’s development is still in its early stages, the researchers noted that “even modest increases in [frataxin] protein are predicted to improve neuronal [nerve cell] and cardiac [heart] function and partially relieve symptoms in FA patients.”
As such, “this approach has the potential to improve both quality of life and life expectancy for individuals with FA,” the researchers wrote.
The study, titled “Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia,” was published in the journal Molecular Therapy Advances.
FA is a genetic disorder marked by a deficiency in frataxin, a protein essential for the health of mitochondria, which are the compartments within cells that generate energy. Without sufficient frataxin, mitochondrial function is compromised, particularly affecting cells with high energy demands — such as nerve and heart muscle cells.
Skyclarys doesn’t directly treat heart problems
Skyclarys (omaveloxolone), the first treatment approved for FA, aims to improve mitochondrial function but does not address the underlying frataxin deficiency. While that oral therapy can slow the progression of neurological symptoms such as ataxia — a loss of muscle coordination — it does not directly treat heart dysfunction. Heart problems are a major cause of early mortality in FA.
Several experimental gene therapies are now being developed to replace the faulty FXN gene, which codes for frataxin, with a healthy version of the gene. However, these approaches generally target either the nervous system or the heart, but not both.
“A key challenge for FA therapeutic development has been targeting both neuronal and cardiac manifestations,” the researchers wrote.
To overcome these limitations, a team at Sanofi developed a strategy called engineered cross-correction, designed to restore frataxin function across multiple tissues and address both neuronal and cardiac dysfunction in FA.
Similar to other gene therapies, the approach uses an adeno-associated virus (AAV) to deliver a functional version of FXN. However, the researchers modified the gene so that treated cells produce a form of frataxin that can be secreted and taken up by neighboring cells. These initially treated cells act as a kind of factory cells, supplying frataxin to other cells.
The therapy is administered into the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord, allowing direct access to the nervous system. But it also takes advantage of the natural leakage of AAV particles from the CSF into the bloodstream, enabling simultaneous delivery to heart muscle cells, the researchers noted.
The treatment was first assessed in two FA mouse models, one lacking frataxin in nerve cells and another lacking it in muscle tissue.
Untreated mice lacking frataxin in nerve cells developed motor coordination problems and progressive ataxia starting at about 10 weeks of age. When treated at the age of 5 weeks, these mice showed a near-complete rescue of these motor deficits.
These data demonstrate that [this new gene therapy] …. can rescue neuronal and cardiac [features] associated with FA, a milestone previously not achieved with … gene therapy candidates.
Mice without frataxin in muscle cells had a significantly reduced lifespan due to impaired heart function. Treatment with AAVs carrying the genetic instructions for natural frataxin failed to improve survival. However, mice given the gene coding for the secretable frataxin lived significantly longer. These effects occurred despite low levels of AAV reaching the heart, the researchers noted.
“These data demonstrate that intra-CSF AAV-FXN engineered for cross-correction can rescue neuronal and cardiac [features] associated with FA, a milestone previously not achieved with small molecule or gene therapy candidates,” the researchers wrote.
Testing whether this new gene therapy could translate to humans
To explore whether this strategy could translate to humans, the team administered the therapy via CSF injection to healthy nonhuman primates (NHPs). The treatment was well tolerated, with no adverse clinical events reported.
Analyses showed that the AAV reached brain regions commonly affected in FA, including the dentate nucleus, as well as the dorsal root ganglia of the spinal cord. It was also detected in six distinct regions of the heart, with broader AAV distribution linked to higher FXN gene activity.
Importantly, frataxin levels did not exceed a twentyfold increase, a threshold previously associated with toxicity.
In heart muscle cells, frataxin protein levels rose by at least 60% in about half of the samples and by at least 30% in nearly all of them. Only mature frataxin was detected in mitochondria, indicating that the added secretion signals were properly removed by normal cellular processing, according to the researchers.
The scientists noted that, based on previously published data, a 60% increase in frataxin would likely fully rescue FA symptoms, while a 30% increase could provide durable symptom relief when combined with residual frataxin production.
“We propose an alternative gene therapy paradigm — Engineered Cross-Correction — for broad therapeutic protein delivery that is both precise and scalable,” the researchers concluded.
