Single-domain antibody-based protein degrader for synucleinopathies

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Synucleinopathies are neurodegenerative disorders marked by alpha-synuclein (α-syn) aggregation in the brain.
• Current treatments for synucleinopathies primarily manage symptoms, lacking disease-modifying cures.
• Limited brain penetration of conventional antibodies poses a challenge for antibody-based therapies.

Purpose of the Study:

• To develop a single-domain antibody (sdAb)-based protein degrader targeting α-syn for enhanced degradation.
• To investigate the therapeutic potential of this sdAb derivative in clearing α-syn aggregates.
• To evaluate the efficacy of sdAbs in overcoming brain entry limitations of larger antibodies.

Main Methods:

• Engineered an sdAb derivative to simultaneously bind α-syn and Cereblon (CRBN).
• Utilized the CRL4^CRBN E3 ubiquitin ligase complex to induce α-syn ubiquitination.
• Assessed proteasomal degradation of α-syn in primary neuronal cultures and mouse models.

Main Results:

• The sdAb-based protein degrader effectively promoted proteasomal degradation of α-syn.
• Enhanced clearance of α-syn was observed in both in vitro and in vivo models.
• The developed therapeutic candidate demonstrated improved α-syn clearance beyond endogenous lysosomal pathways.

Conclusions:

• The novel sdAb-based protein degrader represents a promising therapeutic strategy for synucleinopathies.
• Targeting α-syn for proteasomal degradation offers a viable approach to disease modification.
• sdAbs show potential for enhanced brain penetration, improving therapeutic outcomes for neurological disorders.