Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).
The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.
However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.
"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.
When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.
In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.
"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.
The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.