Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Area of Science:

• Neuroscience and Neurology
• Regenerative Medicine
• Drug Discovery and Development

Background:

• Symptomatic treatments exist for Parkinson's disease (PD) and Alzheimer's disease (AD), but cures or disease-modifying therapies remain an unmet need.
• Current research paradigms focus on antibodies targeting pathological protein aggregates (e.g., alpha-synuclein, amyloid, tau), often yielding promising preclinical results but failing in clinical trials.
• This discrepancy suggests limitations in current approaches for chronic neurodegenerative diseases.

Purpose of the Study:

• To review reasons for clinical trial failures in disease modification for neurodegenerative diseases.
• To propose a novel, uniform regenerative and reparative therapeutic approach.
• To highlight the potential of targeting the repulsive guidance molecule A (RGMA) pathway for neurorestoration.

Main Methods:

• Review of existing literature on clinical trial outcomes for neurodegenerative disease modification.
• Analysis of current research paradigms, including antibody-based strategies against proteinopathies.
• Examination of the role of the RGMA pathway in neuronal restoration and its therapeutic potential.

Main Results:

• Experimental studies show that therapeutic antagonism of RGMA can reverse neurodegeneration in rodent and monkey models.
• Antibodies targeting RGMA are available, with early clinical studies initiated for acute neurological conditions.
• RGMA antagonism stimulates an endogenous repair system, offering a disease-modifying approach independent of specific disease mechanisms.

Conclusions:

• A regenerative approach stimulating endogenous repair systems, specifically via RGMA antagonism, offers a promising alternative to protein-targeting therapies for chronic neurodegenerative diseases.
• Future clinical trials should focus on well-characterized patient cohorts and utilize objective assessments to validate RGMA antagonism's efficacy in stimulating neurogenesis and reversing neurodegeneration.
• This strategy could significantly enhance therapeutic options for chronic neurodegeneration.