Biomarkers Demonstrate Potential as Indicators of HD Progression

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine that is repeated multiple times. Normal persons have a CAG repeat count of between seven and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down by the cell into toxic peptides, which contribute to the pathology of the syndrome.

Although genetic testing readily identifies those who will be affected by HD, current drug treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression of the disease and the inability to biopsy the affected tissue, the brain. These factors make it difficult to design short and effective proof of concept clinical trials to assess treatment benefit.

One of the earliest events in HD is disruption of mitochondrial function by mutant huntingtin aggregates that reduce cellular energy levels and cause oxidative damage. Investigators at Stanford University (Palo Alto, CA, USA) had previously identified a molecule, P110, which could restore mitochondrial function and prevent neuronal death in mouse models of HD. The current study focused on identifying peripheral biomarkers that would correlate with the progression of the disease and treatment benefit.

Initially, the investigators compared levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues in wild-type mice and in the R6/2 HD mouse model. Changes in amounts of these indicators were monitored during P100 treatment of the HD mice.

Results published in the November 7, 2016, online edition of The Journal of Experimental Medicine revealed that P110 treatment effectively reduced the levels of all these biomarkers. Abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects, which suggested that these potential peripheral biomarkers might be candidates to assess HD progression and the benefit of intervention for future clinical trials.

“We have identified several biomarkers that correlate with disease progression and treatment in mice,” said senior author Dr. Daria Mochly-Rosen, professor of chemical and systems biology at Stanford University. “We hope that our work will provide the basis for a larger study of patient samples that may ultimately identify biomarkers that can be used as surrogate markers to determine the benefit of therapeutic interventions in diagnosed but asymptomatic HD patients to prevent or delay disease onset.”

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