Some patients with Huntington’s disease are unluckier than others. While the neurodegenerative disease is known to be caused by 36 or more uninterrupted CAG repeats in the HTT (huntingtin) gene, people with a specific genetic variant, known as the CAG and CCG loss-of-interruption (CAG-CCG LOI), have an early onset of the disease up to 12.5 years earlier.
Researchers didn’t know why — until a new paper published in Neuron, led by Michael Hayden’s group at the University of British Columbia. “This work answers that question,” said Hayden in the press release. His team showed that patients with the CAG-CCG LOI variant had up to five times more expansions of the HTT gene specifically in their medium spiny neurons within the striatum.
“[The work] provides dramatic evidence that repeated expansion of the mutation is an important driver of Huntington disease and a potential treatment target,” said Hayden.
Where the expansion was found
By investigating blood, bulk brain tissue, and striatal medium spiny neuron samples using short-read sequencing and a novel triplet-primed small-pool PCR (TPSP-PCR) assay, the researchers showed that the HTT mutation found throughout cells in the body only leads to significant expansion in brain cells.
“The mutational expansion seems to be selective for the brain,” Hayden said. “That may help explain why Huntington disease, even though the mutation is in every cell, is fundamentally a brain disease.”
But their analysis showed it wasn’t just anywhere in the brain; the CAG-CCG LOI variant led to significant increases of HTT expansion specifically in the striatal medium spiny neurons known to be affected first in Huntington’s disease.
The team also showed that this increase in HTT expansion goes off the rails in early-onset patients and is associated with earlier loss of the medium spiny neurons and depletion of the dopamine receptor 2. Now, the research team needs to identify what causes the variant to lead to such strong expansion.
Targeting the DNA expansion
The findings suggest that targeting repeat expansion of DNA is a worthwhile target in Huntington’s disease, and could perhaps one day be targeted earlier in people with the CAG-CCG LOI variant.
Several companies are already working towards this goal. Latus Bio and Passage Bio are currently testing gene therapy options in preclinical models to directly limit the expansion, while Skyhawk Therapeutics is advancing a small molecule pill currently in a Phase 1/2 clinical trials. Skyhawk recently announced results showing that patients taking their pill showed significant improvements on Huntington’s disease rating scales.
"If we can suppress that expansion, it may be possible to delay progression or delay the onset of disease,” said Hayden.
