AAV9 Viral Vector for SRSF1 Inhibition in Sporadic ALS
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Solution Overview
Problem
Current gene therapy approaches for neurodegenerative diseases like ALS and FTD face challenges in safely delivering genetic material to target neuronal cells, particularly in sporadic cases not caused by C9ORF72 hexanucleotide repeat expansions, with existing methods potentially causing neurotoxicity and lacking effective treatment options.
Innovation Solution
A viral vector is designed with a transcription cassette and non-expressed nucleotide sequences to deliver a nucleic acid molecule encoding an antagonistic agent targeting Serine/Arginine Rich Splice Factor 1 (SRSF1), using AAV vectors to inhibit SRSF1 expression, thereby providing neuroprotection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If viral vectors are used to deliver genetic material for gene therapy, then treatment efficacy for neurodegenerative diseases is improved, but safety risks increase due to potential neurotoxicity and genotoxic effects
Solution Approach 1:
The patent uses AAV serotype 9 as a viral vector intermediary to deliver the antagonistic agent against SRSF1. The AAV9 vector serves as a safe delivery vehicle that can cross the blood-brain barrier and target neuronal cells without causing significant neurotoxicity, thereby resolving the contradiction between treatment efficacy and safety risks
Solution Approach 2:
The patent employs self-complementary AAV (scAAV) construction which changes the replication parameter of the viral vector. The scAAV can replicate its genome without requiring helper viruses, reducing immunogenicity and safety risks while maintaining treatment efficacy through sustained expression of the therapeutic antagonistic agent
2Reliability
If SRSF1 is depleted to treat C9ORF72 repeat expansion ALS, then pathological RNA export is inhibited, but neuroprotection in sporadic ALS cases is not achieved
Solution Approach 1:
The patent develops a universal therapeutic approach by targeting SRSF1, which serves multiple functions: it depletes pathological C9ORF72 repeat transcripts in C9ALS/FTD cases and simultaneously provides neuroprotection in sporadic ALS cases. This single therapeutic strategy achieves multi-functionality across different ALS subtypes, resolving the contradiction between disease-specific efficacy and broad adaptability
3Productivity
If non-expressed stuffer sequences are added to viral vectors, then packaging efficiency is improved, but vector complexity increases
Solution Approach 1:
The patent incorporates non-expressed stuffer sequences into the AAV vector genome to increase packaging capacity and improve production efficiency. These stuffer sequences are disposable elements that do not need to be functional in the final product, allowing optimization of manufacturing without compromising therapeutic function, thereby resolving the contradiction between productivity and complexity
Data Source
AI summary
The present disclosure relates to antagonists that target, directly or indirectly, Serine/Arginine Rich Splicing Factor 1 (SRSF1); viral vectors comprising a nucleic acid sequence encoding SRSF1 antagonists. The use of said vector in gene therapy for the treatment of neurodegenerative diseases such as for example Amyotrophic Lateral Sclerosis (ALS) or sporadic Amyotrophic Lateral Sclerosis which is not caused by a pathological C9ORF72 hexanucleotide repeat expansion and methods thereof are also disclosed.