Regulated gene therapy restores nerve function in Friedreich’s ataxia mice
Mouse study links controlled frataxin levels to better movement and cell health
Written by |
A new gene therapy designed to restore frataxin protein to near-normal levels rather than produce excessive amounts improves movement, nerve signaling, and cell health in a mouse model of Friedreich’s ataxia (FA), a study reports.
The treatment, called miniFXN7, was delivered in a single injection before symptoms began and used the FXN gene’s own natural control switches to keep frataxin production within or close to its normal range, addressing a longstanding concern that too much frataxin can damage cells.
Controlled frataxin replacement may offer safer path forward
“Our findings support a gene therapy strategy based on controlled, physiologically regulated FXN replacement,” the researchers wrote. “This approach provides a path for next-generation therapeutic development in FA, emphasizing the importance of maintaining FXN expression within its optimal functional range.”
The study, “Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia,” was published in Human Gene Therapy.
Most cases of FA are caused by changes in the FXN gene, which reduce production of frataxin, a protein essential for the function of mitochondria, the structures that produce energy for cells. A lack of frataxin impairs mitochondria and damages nerve cells involved in sensation, balance, and movement, leading to disease symptoms.
Despite advances in the understanding of FA, therapeutic options remain limited. Gene therapies that deliver a working copy of the FXN gene to cells have shown benefit in animal studies, but many first-generation AAV gene therapy approaches use strong promoters to drive high levels of frataxin production. Excessive frataxin levels can cause mitochondrial dysfunction and tissue damage, particularly in the heart.
To address this, researchers in France designed a “mini” version of the human FXN gene, called miniFXN7, which incorporates the gene’s natural regulatory sequences that help control frataxin production. The construct was packaged into an adeno-associated virus vector called AAV-PHP.eB for delivery to the nervous system via a single injection into the bloodstream.
“This design aims to achieve physiologically constrained expression,” the team wrote, by preserving the FXN gene’s “intrinsic regulatory architecture.”
Researchers test miniFXN7 before symptoms begin
The researchers tested the therapy in a well-established mouse model that loses frataxin in certain nerve cells, reproducing key features of the human disease. Mice received a single injection at 3.5 weeks of age, before symptoms appeared, and researchers then monitored motor performance and nerve signaling over time and assessed cellular health at 13.5 weeks of age.
Untreated FA mice began to lose motor function around 7.5 weeks of age and reached humane endpoints by around 16 weeks, while mice treated with miniFXN7 remained stable. Treated mice performed about as well as healthy mice on a hanging-wire test of hindlimb function and made fewer missteps than untreated FA mice on a balance test.
Treatment also restored the H-wave, a measure of the reflex pathway that carries sensory signals into a motor response, to the healthy range. At the same time, M-waves, which reflect peripheral motor nerve activity, were similar across all groups.
Under the microscope, researchers found that about half of the neurons in the dorsal root ganglia — clusters of sensory nerve cells near the spinal cord that are affected in FA — were reached by miniFXN7. Frataxin levels increased mostly in the largest neurons, a group that includes proprioceptive nerve cells, which help the body sense its position and movement and are also affected by the disease.
In Purkinje neurons — important cells in the outer layer of the cerebellum that help coordinate movement and are affected in FA — treatment was more limited. MiniFXN7 reached about 25% of Purkinje neurons in the front of the cerebellum and up to 40% in the back. Even so, frataxin levels in these cells were similar to those in healthy mice.
MiniFXN7 reached 70%-80% of neurons in the dentate nucleus, a deep part of the cerebellum and a major output center that is severely affected in FA. Frataxin levels there were higher than those in healthy mice.
“These findings suggest that preservation of dentate nucleus function may disproportionately contribute to functional recovery,” the team wrote.
Treatment improves mitochondrial function and cell health
Treatment also restored the activity of an FA-impaired mitochondrial enzyme to levels similar to those in healthy controls in both the dorsal root ganglia and Purkinje neurons. In addition, mitochondria showed less of the rounded shape associated with cellular stress in all three types of nerve cells examined.
miniFXN7 also preserved nerve cells and reduced signs of inflammation in the cerebellum. In treated mice, Purkinje neurons retained calbindin levels similar to those in healthy mice, consistent with preserved cell health, and showed less astrogliosis, a reactive response involving astrocytes, support cells in the nervous system that respond to injury and disease.
In the dentate nucleus, treatment preserved parvalbumin-positive neurons and increased the density of connections from Purkinje neurons onto these cells compared with untreated FA mice. It also prevented the astrocyte response seen in untreated disease mice.
Counts of surviving neurons confirmed that miniFXN7-treated mice retained more Purkinje neurons and dentate nucleus neurons than untreated FA mice.
The researchers noted that treatment was given before symptoms appeared and that the AAV-PHP.eB vector used in the study would need to be replaced with a vector suitable for use in people.
The authors wrote that the findings show that “physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue” in this mouse model of FA, supporting further development of gene therapies that aim to restore frataxin within or close to its normal range rather than maximize protein production.
Leave a comment
Fill in the required fields to post. Your email address will not be published.