Functional Nucleic Acid Molecules for Nervous System Disorders
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Solution Overview
Problem
Current treatments for neurodegenerative disorders like Parkinson's Disease lack effective methods to slow or arrest neurodegeneration, with existing therapies such as L-DOPA causing side effects and GDNF delivery showing inconsistent results due to poor distribution and uncontrolled expression.
Innovation Solution
Development of functional nucleic acid molecules that specifically target and enhance the translation of endogenous mRNA sequences for Nurr1, GDNF, cRET, and GBA, using SINEUP technology to increase protein levels without exceeding physiological limits, thereby treating nervous system disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant GDNF is administered to treat Parkinson's Disease, then neuroprotection is achieved, but poor distribution within the parenchyma and unsustainable side effects occur due to high doses required
Solution Approach 1:
The patent uses viral vectors as intermediaries to deliver GDNF genes to target cells in the brain. Instead of directly administering recombinant GDNF protein which distributes poorly, the viral vector mediates gene delivery to enable local production of GDNF at the site of injection, improving distribution and reducing the need for high systemic doses
Solution Approach 2:
The patent employs genetic modification approaches where GDNF gene expression is activated under specific promoters (such as dopa-responsive promoters) that allow preliminary setup of controlled expression systems. This enables GDNF to be produced only when and where needed, preventing uncontrolled overexpression and associated side effects
2Reliability
If GDNF expression is increased through viral vectors to achieve efficacy in PD animal models, then neuroprotection is improved, but uncontrolled and ectopic GDNF overexpression occurs resulting in safety issues
Solution Approach 1:
The patent employs dynamic control of GDNF expression through inducible and responsive promoter systems. The dopa-responsive promoter allows GDNF expression to dynamically adjust based on dopamine levels and neuronal activity, ensuring expression remains within physiological ranges rather than being constitutively high
Solution Approach 2:
The patent implements feedback control mechanisms where GDNF expression is regulated by dopamine-responsive elements. When dopamine levels are sufficient, GDNF expression is downregulated; when dopamine levels are low (as in PD), GDNF expression is upregulated, creating a self-regulating system that prevents overexpression
3Ease of operation
If L-DOPA is used as the gold standard for symptomatic treatment, then motor symptoms are improved, but side effects and resistance develop over time
Solution Approach 1:
The patent uses GDNF as an intermediary to protect and support dopamine neurons, addressing the root cause of Parkinson's rather than just symptoms. GDNF acts as a neurotrophic factor that promotes neuronal survival and function, providing a complementary mechanism to L-DOPA that does not suffer from the same tolerance and side effect issues
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 increases protein synthesis of Nurr1, GDNF, cRET, and GBA, potentially offering neuroprotection and reducing side effects by modulating protein expression within physiological ranges, providing a more targeted and safer therapeutic option for neurodegenerative diseases.
Implementation Method 1
at least one target binding sequence comprising a sequence reverse complementary to a target mRNA sequence
Data Source
AI summary
The invention relates to therapeutic agents which enhance protein translation of an endogenous mRNA sequence, particularly for use in a method of treating a disease or disorder of the nervous system. In particular, the therapeutic agent is a functional nucleic acid molecule comprising at least one target determinant sequence and at least one regulatory sequence.