In Friedreich’s Ataxia, Neurotrophins Hold Therapeutic Potential to Prevent, Treat Neurodegeneration

Researchers have demonstrated in the lab (in vitro) and in living subjects (in vivo), that gene transfer of brain-derived neurotrophic factor (BDNF) protected models of Friedreich’s ataxia from neuronal degenerative death, providing a proof of principle that neurotrophins might be a therapeutic option to prevent and treat neurodegeneration associated with Friedreich’s ataxia.

The research paper, “Gene transfer of brain derived neurotrophic factor (BDNF) prevents neurodegeneration triggered by frataxin deficiency,” was published in Molecular Therapy.

Friedreich’s ataxia is a neuromuscular disease characterized by progressive neurodegeneration of nerves and muscles in the nervous system and heart, and is caused by mutations in the FXN gene that lead to decreased transcription of the gene locus and, consequently, low levels of frataxin (FXN), a protein important for anti-oxidative defense by cells. Therapeutic strategies under development focus on different approaches, such as raising FXN levels within cells, through drugs, or by gene therapy by re-introducing the normal FXN gene or activating the silenced gene.

Another promising strategy might be the prevention of neuronal apoptosis (cell death), a therapeutic approach that has been suggested as a promising strategy to treat neurodegenerative diseases. Neurotrophic factors are secreted proteins that are able to stop apoptosis and enhance neuronal function, properties that have made them the subject of research for therapies for neurodegeneration and traumatic injuries.

Researchers used gene therapy techniques to design a vector carrying the gene encoding for brain-derived neurotrophic factor (BDNF) and test its effect in frataxin-deficient neurons both in vitro and in the mouse cerebellum in vivo. In vitro results indicated the gene transfer of BDNF prevented the death of neurons usually caused by the lack of frataxin. Moreover, researchers also confirmed this neuroprotective effect in vivo in a mouse model where frataxin knockdown is accompanied by significant neuronal death and loss of motor coordination. Injection of the vector carrying the BDNF gene prevented not only cerebellar neurodegeneration but also the ataxic phenotype.

Researchers concluded that this study provides “evidence for the therapeutic potential of neurotrophins like BDNF to treat neurodegeneration in Friedreich’s ataxia. Viral vector-mediated gene encoding for neurotrophic factors may be therefore considered as an additional tool to current gene and cell therapy approaches which are now in progress.”