Antisense Oligonucleotides Modulating LRRK2 Splicing for Parkinsons
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Solution Overview
Problem
Current treatments for Parkinson's disease, particularly those targeting LRRK2 gene mutations, are inadequate in effectively alleviating symptoms, as existing therapies do not fully address the underlying kinase activity issues caused by mutations like G2019S and R1441C, leading to incomplete symptom relief and potential toxicity.
Innovation Solution
Development of antisense oligonucleotides (ASOs) that specifically target and modulate the splicing of LRRK2 gene transcripts, inducing skipping of exons 31 and 41 to reduce kinase activity, thereby mitigating the toxic effects of mutated proteins and improving symptom management.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies targeting LRRK2 gene mutations are used, then some symptom relief is achieved, but the underlying kinase activity issues are not fully addressed leading to incomplete symptom relief and potential toxicity
Solution Approach 1:
The patent extracts and removes the harmful mutated exons (exon 31 containing R1441C mutation and exon 41 containing G2019S mutation) from the LRRK2 transcript through antisense oligonucleotide-mediated exon skipping. This selectively eliminates the toxic mutated protein while preserving the rest of the functional protein, thereby reducing toxicity while maintaining necessary kinase activity for symptom relief.
Solution Approach 2:
The invention applies local quality by using mutation-specific antisense oligonucleotides that target only the specific mutated regions (exon 31 for R1441C, exon 41 for G2019S). This localized approach allows differential treatment of different mutation types, achieving effective symptom relief for each mutation type while minimizing off-target effects and toxicity.
2Object-generated harmful factors
If exon skipping is induced to reduce kinase activity, then toxic effects of mutated proteins are mitigated, but complete elimination of kinase activity may compromise necessary cellular functions
Solution Approach 1:
The patent converts the harmful overactive kinase activity into a beneficial state by using the antisense oligonucleotide-induced exon skipping to reduce kinase activity to an optimal level. The mutated exons are skipped to decrease pathogenic kinase activity, yet enough kinase function is preserved to maintain necessary cellular functions, effectively converting the harmful gain-of-function into a therapeutic benefit.
Solution Approach 2:
The invention changes the kinetic parameter of LRRK2 by modulating kinase activity levels through selective exon skipping. Rather than completely eliminating kinase activity, the antisense oligonucleotides adjust the activity parameter to a therapeutic range that reduces toxic effects while preserving essential cellular functions, achieving a balanced parameter optimization.
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 use of ASOs effectively reduces LRRK2 protein expression and kinase activity, leading to improved symptom relief and potential therapeutic benefits for Parkinson's disease patients with LRRK2 mutations, such as enhanced neurite outgrowth and calcium homeostasis.
Implementation Method 1
compounds comprising oligonucleotides complementary to a LRRK2 RNA transcript... such hybridization results in modulation of splicing of the LRRK2 transcript
Data Source
AI summary
The present disclosure relates generally to compounds comprising oligonucleotides complementary to a Leucine-Rich-Repeat-Kinase (LRRK2) RNA transcript. Certain such compounds are useful for hybridizing to a LRRK2 RNA transcript, including but not limited to a LRRK2 RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the LRRK2 transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Parkinson's disease.