hnRNP L Modulation for Cryptic Exon Splicing Defects
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Solution Overview
Problem
Current treatments are inadequate for neurological disorders caused by cryptic exon-induced diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) due to misregulation of RNA Binding Proteins like hnRNP L and TDP-43, leading to splicing defects and proteinopathies.
Innovation Solution
Administering agents to increase the expression and stability of hnRNP L using delivery vehicles like liposomes or nanoparticles to correct splicing defects and reduce cryptic exon inclusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for neurological disorders caused by cryptic exon-induced diseases, then treatment coverage is limited, but splicing defects and proteinopathies persist
Solution Approach 1:
The patent uses antisense oligonucleotides (ASOs) as intermediary molecules that bind to specific RNA sequences involved in cryptic exon inclusion. These ASOs act as mediators between the therapeutic goal (correcting splicing defects) and the molecular target (aberrant splicing patterns), enabling targeted treatment of splicing defects without affecting other cellular processes.
Solution Approach 2:
The patent modifies splicing parameters by changing the binding affinity and specificity of oligonucleotide therapeutics to different splice site sequences. By adjusting parameters such as oligonucleotide sequence composition, length, and chemical modifications, the treatment can be optimized to target specific cryptic exons while preserving normal splicing of other genes.
2Manufacturing precision
If agents are administered to increase hnRNP L expression, then splicing accuracy improves, but delivery complexity increases
Solution Approach 1:
The patent employs delivery vehicles such as liposomes, nanoparticles, or viral vectors as intermediaries to transport hnRNP L-modulating agents across the blood-brain barrier and into target cells. These delivery systems mediate the complex task of getting therapeutic agents into the central nervous system while protecting the agents from degradation and enabling controlled release.
Solution Approach 2:
The patent utilizes liposomal and nanoparticle delivery systems with flexible membrane structures that can encapsulate therapeutic agents and navigate biological barriers. These flexible shell structures protect the cargo while allowing for cellular uptake and targeted delivery to affected neurons and glial cells.
3Reliability
If splicing defects are corrected by increasing hnRNP L levels, then cryptic exon inclusion decreases, but treatment specificity must be maintained
Solution Approach 1:
The patent applies local quality by designing oligonucleotide therapeutics with sequence specificity tailored to each patient's unique splicing defect. Each treatment is customized to target the specific cryptic exon inclusion event in that patient, ensuring that the therapeutic effect is localized to the precise molecular error without affecting other splicing events throughout the genome.
Solution Approach 2:
The patent modifies treatment parameters by adjusting oligonucleotide sequence composition, concentration, and chemical modifications to achieve optimal specificity for each patient's splicing defect. By changing these parameters, the treatment can be fine-tuned to correct the specific cryptic exon inclusion while minimizing off-target effects on other genes.
Data Source
AI summary
Disclosed are methods of treating a subject with a neurological disease associated with a splicing defect caused by TDP-43 proteinopathies, comprising administering to said subject an agent to increase expression levels and/or stability of hnRNP L, thereby attenuating and/or repairing the splicing defect. The disclosure also relates to nucleic acids targeting heterogeneous nuclear ribonucleoprotein L (hnRNP L), and their use.