Disease Progression Biomarkers: Huntington’s Disease

Biomarkers play an integral role in the success rates of drug development, serving a wide range of applications from monitoring disease progression to guiding clinical decisions. In fact, over 80% of projects utilizing efficacy biomarkers showed activity of success in Phase IIa, compared to less than 30% without such biomarkers.¹

Navigating the landscape of biomarker discovery is challenging, particularly for neurological diseases owing to brain complexity, the blood-brain barrier (BBB) and limited accessibility to relevant pathological tissues. The early onset of neurological diseases before symptoms, the lack of established models for validation and the prolonged development timelines for central nervous system (CNS) drugs exacerbates these challenges.

While biomarkers in cerebrospinal fluid offers a solution to some of these challenges, such procedures are highly invasive to patients. The search for less intrusive and more accessible alternatives, such as blood-based biomarkers, are therefore of significant interest in neurology. In this use case, we explore potential blood biomarkers for the progression of Huntington’s Disease (HD), a rare neurological condition.

HD is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric symptoms.² HD progressively worsens over time, generally proving fatal around 20 years after symptom onset.³ Biomarkers of disease progression are essential for accurately monitoring disease status and assessing the impact of therapeutic strategies.

By leveraging AI, Causaly can expedite the identification and prioritization of biomarkers for neurological diseases. Over 250 potential biomarkers of disease progression in HD were identified by Causaly. Approximately 40 of these were potential blood biomarkers of HD progression reported in the literature over the last 5 years. By prioritizing biomarkers, Glial Fibrillary Acidic Protein (GFAP) was selected as a recently reported biomarker of interest.

GFAP, a type III intermediate filament protein primarily expressed in astrocytes, is crucial for CNS structural integrity. Its overexpression, indicative of CNS injury,⁴ highlights its promise as a biomarker for astrogliosis – a condition marked by astrocyte proliferation due to neural damage.

In a recent study within a cohort of Chinese HD mutation carriers, plasma GFAP levels correlated with Neurofilament Light Chain (NfL) in tracking disease burden and could effectively distinguish between carriers and non-carriers.⁵ This highlights the potential of GFAP as a blood-based biomarker for monitoring HD progression. However, further studies are required to assess the clinical utility of GFAP as a biomarker for this disease.

Although challenging, the development of biomarkers, particularly blood biomarkers, for neurodegenerative diseases is a critical endeavor. Biomarkers hold a fundamental role in enhancing disease understanding and offering reliable methods for tracking disease progression. As the global neurological biomarkers expected to hit $8 billion in 2023,⁶ biomarkers pave the way for improved targeted and efficacious treatments.

While significant progress has been made in the exploration of blood biomarkers in neurology, sustained and collaborative scientific efforts are required for further advancements. Causaly can address this by streamlining the identification of promising biomarkers, enabling drug discovery projects to transition into clinical programs with confidence.