Using a gene therapy strategy similar to one previously shown to reverse heart problems in a Friedreich’s ataxia mouse model, researchers also corrected sensory symptoms associated with the disease in another mouse model. These results suggest that gene therapy may effectively treat different features of Friedreich’s ataxia.
Hélène Puccio with the Institut de Genetique et de Biologie Moleculaire et Cellulaire, in Illkirch, France, presented the results in the study “Correction of sensory ataxia in a novel mouse model of Friedreich ataxia using gene therapy approach” on Saturday, the closing day of IARC 2017. (A taped interview with Dr. Puccio follows this article.)
IARC, the International Ataxia Research Conference, opened in Pisa, Italy, on Wednesday.
Low levels of frataxin, an essential mitochondrial protein, is the cause of Friedreich’s ataxia (FA), the most common inherited recessive ataxia. The disease is characterized by nervous system damage, movement problems, and hypertrophic cardiomyopathy (enlargement of the heart muscle).
In FA patients, tissues most affected are heart muscle cells called cardiomyocytes, and proprioceptive neurons within the dorsal root ganglia, or neurons within spinal ganglions that act as sensors, providing information to the central nervous system.
Puccio and colleagues have been investigating a gene therapy approach as a potential treatment for FA cardiomyopathy using adenoviruses carrying genetic information — in this case, the frataxin gene — to target cells.
Viral vectors like adenoviruses can be used as vehicles (or vectors) to deliver a functional frataxin gene into specific cells, so that higher levels of frataxin protein can be produced. The viruses are modified to prevent them from causing disease.
In a previous study, the researchers showed that an adenovirus expressing human frataxin, when injected intravenously (into the bloodstream) of an FA mouse model effectively and completely reversed cardiac disease.
The gene therapy was seen to rapidly rescue the normal characteristics of heart cells, suggesting that the same therapeutic approach might be of benefit to other cells affected by low frataxin levels.
So, the researchers generated a new mouse model, one that mimics the sensory impairments experienced by Friedreich’s ataxia patients by deleting the frataxin gene from two specific populations of cells in the nervous system.
These mice “mimic the propioceptive impairment … an impairment in what gives you the position of the body. This is one of the first impairments affecting FA patients,” Puccio said.
Propioceptive impairment occurs “in the dorsal root ganglia, and that is particularly what we have [captured] in the new mouse model … that gives us sensory ataxia,” she said.
Researchers injected the animals intravenously with an adenovirus expressing human frataxin, and found that the treatment completely prevented the onset of sensory ataxia symptoms.
Further analysis showed that mice receiving the gene therapy maintained their sensory capacities. In one of the two most-affected tissues in Friedreich’s ataxia patients — the dorsal root ganglia — nerve cell death was not evident, meaning it appeared to have been prevented by the treatment.
“We were able to show that we can prevent neuron degeneration, but we can also rescue neurons that have already degenerated,” Puccio told Friedreich’s Ataxia News in an interview, referring to neurons in the dorsal root ganglia.
Next, the researchers investigated how effective gene therapy might be if applied at a later disease stage, using mice with evident FA symptoms.
They found that a combination of adenovirus, delivered intravenously, plus a triple infusion of adenovirus into the brain reversed key symptoms of Friedreich’s ataxia disease — a reversal seen in results of gait analysis, coordination tests, and electromyography analysis (a diagnostic procedure that assesses the health of muscles and motor neurons).
The therapy also preserved neurons and prevented damage to nerve cells.
“When we treated the mouse post-symptomatically, we were able to reverse the ataxia phenotype, so they [the animals] became less ataxic, reverse the loss of sensory wave … and actually extend the life span of the animal,” Puccio said.
But, she added, “we weren’t able to correct completely everything, because there is also a cerebellar phenotype that we were able to [only] partially correct.”
Based on results obtained so far, the team believes that gene therapy is a valid and promising approach to addressing sensory ataxia.
The next step, Puccio said, “is to try to see how we can translate this into humans,” and develop “more clinical-grade vectors and then test dose-response.”
Gene therapy “is something very promising,” she said, “but I also think it’s important to continue moving forward on pharmacological approaches also, because we don’t know if gene therapy will be able to hit all the cells that need to be hit.”
Rather, “I think both approaches [gene and drug therapies] need to be continued to be developed,” she concluded.
Friedreich’s Ataxia News had the opportunity to interview Dr. Puccio at IARC 2017.
The complete interview can be seen below: