“Several therapies in clinical trials have shown an unexpected immediate benefit — of days to a few weeks — especially improvement in fatigue and speech, very different from the slow disease progression based on neuronal loss,” David Lynch said. “These results imply that our understanding of Friedreich’s ataxia neuropathology is limited, in that some neurological deficits in FA are more readily modifiable at the early stage of disease.”
David Lynch, professor of neurology at the Children’s Hospital of Philadelphia, was awarded an MDA research grant totaling $300,000 over three years to improve understanding of neurological dysfunction in Friedreich’s ataxia (FA).
FA is caused by deficiency of the mitochondrial protein frataxin. To date, a number of clinical trials to test mitochondrial enhancers and frataxin restoration drugs in FA have shown an unexpected short-term response, particularly in speech dysfunction and fatigue. However, speech dysfunction in FA does not stem from brain regions in which cell loss occurs early in the disease. Instead, such deficits may be caused by early synaptic abnormalities. If this is the case, it may be possible to therapeutically target these abnormalities and ameliorate symptoms of speech deficit and fatigue.
In previous studies, Lynch and colleagues have identified early impaired cerebellar mitochondrial biogenesis and synaptic deficits in a mouse model with neurobehavioral deficits analogous to the clinical manifestations observed in people with FA. The team hypothesizes that deficiency of frataxin protein in the cerebellum leads to cerebellar mitochondrial and synaptic deficits that contribute to cerebellar dysfunction and ataxia in FA patients.
Now the team is working to determine if rescuing mitochondrial biogenesis or synaptic deficits can reverse cerebellar dysfunction and neurobehavioral deficits in the FA mouse models.
If successful, this work could improve the understanding of neurological dysfunction in FA, which could immediately translate to novel treatment strategies for FA patients.
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