Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
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