Antisense Oligonucleotides Modulate TOMM TIMM APOE Isoforms
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Solution Overview
Problem
There is a long-standing unmet need for effective therapies to treat neurodegenerative diseases associated with mitochondrial dysfunction, as current treatments are inadequate in addressing the molecular mechanisms contributing to these disorders.
Innovation Solution
The use of antisense oligonucleotides that bind to TOMM, TIMM, or APOE isoform polynucleotides to modulate their function or expression, thereby preventing or treating neurodegenerative diseases such as Alzheimer's, ALS, and Parkinson's disease, by targeting Alu element-induced isoforms and employing CRISPR-Cas9 genome editing to modify or eliminate Alu elements contributing to mitochondrial dysfunction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to modulate TOMM, TIMM, or APOE isoform expression, then neurodegenerative disease risk is reduced, but treatment complexity and delivery challenges increase
Solution Approach 1:
The patent employs antisense oligonucleotides as intermediary molecules that bind to specific polynucleotide sequences of TOMM, TIMM, or APOE isoforms to modulate their expression. These oligonucleotides serve as mediators between the therapeutic goal (reducing neurodegenerative disease risk) and the molecular target (dysfunctional mitochondrial populations), enabling selective modulation without direct genetic manipulation.
Solution Approach 2:
The therapy targets specific isoforms (TOMM, TIMM, APOE) that are segments of the broader mitochondrial dysfunction problem. By segmenting the therapeutic approach to address individual isoforms responsible for dysfunctional mitochondrial populations, the treatment achieves precision while managing complexity through targeted rather than broad-spectrum intervention.
2Stability of the object's composition
If CRISPR-Cas9 genome editing is employed to eliminate Alu elements, then mitochondrial function is stabilized, but off-target effects and genomic safety concerns arise
Solution Approach 1:
The patent uses antisense oligonucleotides to preliminarily modulate the expression of TOMM, TIMM, or APOE isoforms before potentially proceeding to CRISPR-Cas9 genome editing. This preliminary action allows for controlled reduction of dysfunctional isoform levels and assessment of therapeutic effect, thereby mitigating the risk of aggressive genomic editing while stabilizing mitochondrial function.
Solution Approach 2:
The patent acknowledges that Alu elements, while causing dysfunctional mitochondrial populations through alternative splicing, can be targeted therapeutically. By converting the harmful presence of Alu-induced isoforms into a therapeutic opportunity through antisense oligonucleotide binding and CRISPR-Cas9 editing, the treatment transforms the source of mitochondrial dysfunction into the target of stabilization.
3Object-generated harmful factors
If alternative splicing events are targeted to reduce dysfunctional isoforms, then protein aggregate formation is prevented, but specificity in isoform targeting becomes challenging
Solution Approach 1:
The antisense oligonucleotides are designed with specific sequences that bind to unique regions of TOMM, TIMM, or APOE isoform polynucleotides. This local quality approach ensures that each oligonucleotide targets a specific isoform variant with high precision, distinguishing between dysfunctional Alu-induced isoforms and functional variants, thereby preventing protein aggregate formation without affecting normal protein synthesis.
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
This approach effectively modulates the expression of mitochondrial translocase complexes, reducing the risk of neurodegenerative diseases by stabilizing mitochondrial function and preventing the formation of inflammatory protein bodies, thereby addressing the underlying causes of mitochondrial dysfunction.
Implementation Method 1
antisense oligonucleotides that bind to TOMM, TIMM, or APOE isoform polynucleotides to modulate their function or expression
Implementation Method 2
employing CRISPR-Cas9 genome editing to modify or eliminate Alu elements contributing to mitochondrial dysfunction
Data Source
AI summary
Retrotransposons, operating though human-specific neurological pathways, can contribute to environment, lifestyle, and/or age-related neurodegeneration by disrupting functional mitochondrial populations within neurons. The mitochondrial disruption can occur through a number of retrotransposon-induced mechanisms that can influence the efficient and accurate transcription and/or translation of mitochondrial genes encoded in the nuclear genome, operating primarily through epigenetic processes. Alu element-related conformational changes (both subtle and major) of the outer and inner mitochondrial membrane pores can restrict or prevent the normal translocation of proteins (i.e., TOMM and TIMM complexes), ultimately contributing to mitochondrial stress, mitophagy, inflammation, and neuron and glial cell death. Compositions and methods are provided for mitigating and/or preventing Alu element-induced conformational changes to prevent and/or treat neurodegenerative disease and other diseases and disorders associated with at least one TOMM, TIMM, or APOE isoform including cancer and other inflammatory diseases.