Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Altered protein conformation underlies neurodegenerative disorders.
• Mutations in the SERPINI1 gene cause neuroserpin aggregation, leading to neuronal death in Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB).

Purpose of the Study:

• To develop and validate an adenine base editor (ABE)-mediated gene correction strategy for FENIB.
• To assess the efficacy of ABE in correcting the pathogenic SERPINI1 variant and restoring neuronal function.
• To optimize ABE delivery for potential clinical applications in neurodegenerative diseases.

Main Methods:

• Development of HEK293T and induced pluripotent stem cell (iPSC) models of FENIB.
• Utilized a personalized adenine base editor (ABE) to correct the pathogenic SERPINI1 variant.
• Employed an inducible mutant neuroserpin-GFP (MUT NS-GFP) neuron system to study protein aggregation.
• Engineered neuron-specific virus-like particles for enhanced ABE delivery.

Main Results:

• ABE-mediated correction restored neuronal dendritic morphology in FENIB models.
• ABE treatment significantly reduced the size and number of neuroserpin inclusions.
• Early prevention of toxic protein expression facilitated aggregate clearance, while late prevention halted aggregation.
• Neuron-specific viral vectors improved ABE delivery efficiency.

Conclusions:

• Personalized ABE-mediated gene correction is a promising strategy for FENIB.
• This approach shows potential for treating other neurodegenerative diseases caused by protein misfolding, such as Alzheimer's and Huntington's diseases.
• Optimized viral delivery systems are crucial for the clinical translation of gene-editing therapies.