Exon Skipping in VCP Disease via Antisense Nucleic Acids
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Solution Overview
Problem
Current treatments for VCP-associated neurodegenerative diseases, such as Inclusion Body Myopathy with Paget's disease of the bone and Frontotemporal Dementia, lack effective methods to address the progressive muscle weakness and neurodegenerative phenotypes, with existing therapies failing to significantly improve muscle strength and reduce neuropathology.
Innovation Solution
A transgenic CRE-ER™-VCPR155H/+ mouse model is developed, allowing for the targeted excision of the VCP R155H mutation using TAMOXIFEN-inducible Cre recombinase, which administers antisense VCP exon 4 or exon 5 nucleic acids to reduce autophagy markers and apoptosis, thereby ameliorating the disease phenotypes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies are used for VCP-associated neurodegenerative diseases, then treatment is provided, but muscle strength is not significantly improved and neuropathology is not reduced
Solution Approach 1:
The patent changes the molecular parameter of VCP protein expression by using antisense nucleic acids to specifically target and reduce the expression of mutant VCP protein. This parameter change approach allows selective modulation of the disease-causing protein while preserving normal protein function, thereby improving therapeutic efficacy and muscle strength without significant side effects
2Reliability
If VCP expression is reduced using antisense nucleic acids, then muscle strength improves and neuropathology reduces, but the complexity of the treatment approach increases
Solution Approach 1:
The patent introduces antisense nucleic acids as intermediary molecules that mediate between the administration route and the target VCP gene. These intermediaries bind to specific sequences of the VCP mRNA, blocking translation and reducing mutant protein production. This intermediary approach simplifies the overall treatment strategy by providing a direct molecular mechanism to achieve therapeutic effects
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach demonstrates improved muscle strength, reduced neuropathology, and partial rescue of Paget's disease in mice, providing a therapeutic model for VCP-associated neurodegenerative diseases by modulating VCP expression through antisense nucleic acids and Cre-mediated recombination.
Implementation Method 1
Applicants generated a unique CRE-ERTM-VCPR155H/+ TAMOXIFENTM-inducible mouse model. This technology allows determination of the effects of targeted excision of exons 4 and 5, including the R155H mutation, in VCP disease.
Implementation Method 2
Parallel studies using splice switching therapeutics, which exclude or promote retention of specific exons as necessary, have been used successfully in muscle degenerative diseases such as Duchenne muscular dystrophy (DMD-exon skipping) and spinal muscular atrophy (SMA-exon retention).
Data Source
AI summary
Provided herein are methods, compositions and transgenic mice useful in treating and developing treatments for VCP-associated neurodegenerative diseases.