Rehovot, Israel – Researchers from Israel identified novel small molecules that can selectively lower the levels of mutant Huntington (Htt) mRNA and protein in Huntington disease (HD).
These molecules reduced mitochondrial dysfunction, restored the expression of brain-derived neurotrophic factor (BDNF), improved motor function, and reduced anxious-like behavior in a mouse model of the disease.
The study appeared in the preprint server bioRxiv.
Based on these findings, the researchers concluded that lowering the levels of mutant Htt using small molecules could be “an effective therapeutic strategy for Huntington Disease.”
The small molecules in question, SPI-24, and SPI-77, are inhibitors of Spt5-Pol 2, which is involved in transcription elongation and RNA processing. So, its inhibition by SPI-24 and SPI-77 reduces mutant Htt mRNA and protein levels.
The research team led by Rivka Dikstein, PhD, from the Department of Biomolecular Sciences, The Weizmann Institute of Science in Rehovot, Israel, also showed that SPI-24 and SPI-77 could pass the blood-brain barrier.
Moreover, when these molecules were injected under the skin of the mice or administered by mouth in the early stages of the disease, disease progression was significantly delayed.
The researchers also reported that long-term treatment with SPI-24 led to no side effects or global changes in gene expression.
“These SPIs provide a great therapeutic strategy due to their simple delivery, especially when prolonged and safe treatment of HD patients is needed,” the researchers wrote. “Thus, SPIs are excellent candidates for clinical evaluations as a therapy against HD.”
HD is a rare inherited neurological disease caused by a CAG trinucleotide expansion in the first exon of the Htt gene. This expansion results in the production of misfolded protein, which is then cleaved inside cells. The resulting protein fragments form aggregates that are toxic to nerve cells and lead to neuropsychiatric symptoms, progressive movement disorders, and dementia.
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