UK company selects HRN001 as its lead Huntington’s therapy candidate
Experimental treatment could enter clinical testing next year
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U.K. biotech company Harness Therapeutics has selected HRN001 as its lead experimental treatment candidate for Huntington’s disease.
“The nomination of HRN001 represents a pivotal milestone for Harness and underscores our commitment to the Huntington’s disease community,” Jan Thirkettle, PhD, CEO of Harness, said in a company press release.
The therapy works by increasing levels of FAN1, a DNA repair protein shown to help prevent further expansion of Huntington’s-causing CAG repeats in nerve cells — a process called somatic expansion.
“By precisely [increasing] FAN1, a target with compelling genetic validation in delaying disease onset, HRN001 represents a differentiated, first-in-class therapeutic approach for addressing somatic expansion, a fundamental driver of disease progression,” Thirkettle said.
Harness plans to continue preclinical development of the therapy this year, with the goal of moving HRN001 into clinical testing next year. The company has assembled a clinical advisory board of experts to guide the therapy’s development.
“We look forward to advising the Company, as it advances HRN001 toward the clinic, translating this promising science into a clinical programme that could meaningfully alter the course of this devastating disease,” said Irina Antonijevic, MD, PhD, chair of Harness’ clinical advisory board.
HRN001 aims to boost activity of FAN1 gene
Huntington’s is caused by a trinucleotide repeat expansion mutation in the HTT gene, which provides instructions to produce a protein called huntingtin. While this gene typically includes 10 to 35 repeats of a trio of DNA building blocks — a cytosine (C), an adenine (A), and a guanine (G) — people with Huntington’s have an excess number of CAG repeats.
This results in the production of a longer-than-normal version of the huntingtin protein that is toxic to nerve cells. This can lead to a range of symptoms, and the longer the CAG stretch, the earlier and more severe the symptoms tend to be.
Although people with Huntington’s are born with abnormally long CAG repeats, increasing evidence shows that these repeats can grow longer over time in the nerve cells most affected by the disease. This process, somatic expansion, is thought to play a key role in the initiation and progression of Huntington’s.
Harness has worked for years and raised millions to develop a treatment that can slow somatic expansion, potentially slowing Huntington’s progression. The company has focused on the FAN1 gene, a genetic modifier of Huntington’s that influences its onset and progression. Genetic modifiers are genes or genetic variants that can increase or decrease the severity of a condition without necessarily causing the disease.
FAN1 is one of the most compelling and consistently validated genetic modifiers of Huntington’s disease identified to date, with a clear mechanistic link to somatic expansion and disease progression.
Now, Harness has settled on HRN001, which aims to boost FAN1 activity. The lead therapy candidate specifically targets the FAN1 gene’s messenger RNA (mRNA), an intermediary molecule derived from DNA that is used as a template for protein production.
HRN001 was designed using the company’s proprietary MISBA platform, which enables a precise, self-limited increase in FAN1 mRNA levels, thereby preventing excessive FAN1 overproduction that could be damaging.
“FAN1 is one of the most compelling and consistently validated genetic modifiers of Huntington’s disease identified to date, with a clear mechanistic link to somatic expansion and disease progression,” Antonijevic said. “Harness’ approach with HRN001 offers a novel and highly targeted way to therapeutically modulate this pathway.”
In preclinical models of Huntington’s, HRN001 treatment has led to a strong increase in FAN1 levels and a reduction in somatic expansion, according to Harness. The therapy also shows favorable pharmacological and tolerability profiles, the company said.
Preclinical data will be presented by Andy Billinton, PhD, Harness’ chief scientific officer, at the upcoming CHDI Foundation Huntington’s Disease Therapeutics Conference, to be held Feb. 23-26, in Palm Springs, California.
