D-PUFA Drug Candidate Shows Cognitive Improvement in Huntington Disease Patients


An isotopic-reinforced polyunsaturated fatty acids shows a reduction in cognitive deficits in a preclinical in vivo model of Huntington disease.

Characterized by progressive neuron degeneration within 15 to 20 years in adults and rapid neuron degeneration within 5 years in children, treatment for Huntington disease continues to be a substantial challenge for health care providers.

However, isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) may help combat the devastating disease by delivering deuterated polyunsaturated fatty-acid therapeutics that stabilize and “fireproof” mitochondrial and cellular membranes against attack, while restoring cellular health. Simply put, D-PUFAs can potentially protect against free radical damage that causes cell death in many neurodegenerative diseases.

In a recent paper published by The FEBS Journal, RT001, 1 such D-PUFA, was shown to be beneficial in a preclinical in vivo model of Huntington disease. Specifically, RT001, an orally available D-PUFA that incorporates into and stabilizes mitochondrial and cellular membranes, demonstrated a reduction in cognitive deficits while simultaneously downregulating brain lipid peroxidation biomarkers.

“Lipid peroxidation has been implicated in many neurodegenerative diseases for decades,” shared Mikhail Shchepinov, PhD, CSO and co-founder of Retrotope, in a recent statement,

“but it has never been successfully addressed therapeutically.”

In the recently published study, effectiveness of RT001 was evaluated in a knock in mouse model of Huntington disease (Q140), which, according to study authors, presents motor deficits and neuropathology from a few months of age, as well as progressive cognitive decline.

For the study, Q140 knock‐in mice were fed a diet containing either D‐ or H‐PUFAs for 5 months starting at 1 month of age. They found that use of RT001 resulted in an 80% decrease in F2‐isoprostanes in the striatum as compared with H‐PUFA treatment and improved performance in novel object recognition tests, without significantly changing motor deficits or huntingtin aggregation.

By demonstrating its ability to “rescue” the “Q140 knock-in mice,” Retrotope’s RT001 further underscores the notion that D-PUFA drugs deserve consideration as a disease-modifying therapy for multiple intractable neurodegenerative diseases.

“It is now evident from improvements noted in this Huntington model, a placebo-controlled phase 1/2 disease clinical trial in Friedreich’s ataxia, continuing improvement in two Expanded Access subjects with the strictly progressive, fatal disease, infantile neuroaxonal dystrophy, and dozens of specific animal and cell models of diseases, that lipid peroxidation is a validated, druggable target across many diseases of neurodegeneration,” Dr Shchepinov added.

As referenced by Dr Shchepinov, RT001 displayed positive outcomes and findings in previous studies and trials, such as the phase 1b/2a trial which assessed its as a potential treatment for Friedreich’s ataxia.

As such, 2 single-patient, Compassionate Use trials assessing RT001 as a treatment for late onset Tay Sachs (LOTS) disease and familial encephalopathy with neuroserpin inclusion bodies (FEIN or neuroserpinosis) were recently initiated. Clearance from the US Food and Drug Administration for a phase 2/3 clinical trial investigating RT001 as a treatment for infantile neuroaxonal dystrophy (INAD) was also recently received this past June.

“This Huntington disease model now adds to multiple models of major and rare neurodegenerative diseases in which disease-modifying effects have been observed using D-PUFA drug candidates, including improvements in cognition and motor skills,” added Robert Molinari, PhD, CEO of Retrotope. “Due to the essential role of PUFAs in membrane lipid remodeling essential for healthy cells,” he added, “D-PUFAs are everywhere accessible to tissues that need them—an otherwise key obstacle in neurodegeneration. It’s time for the neurology community to embrace this new target class and drug strategies that effectively address it.”

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