ASPA Gene Therapy for Mitochondrial Dysfunction in ALS
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Solution Overview
Problem
There is a pressing need for effective methods to treat, prevent, or reverse amyotrophic lateral sclerosis (ALS), as current treatments only slow progression and no cure is available, with mitochondrial dysfunction being a key contributor to the disease.
Innovation Solution
Administering a composition that increases the expression of aspartoacylase (ASPA) in cells, particularly through gene therapy using a recombinant adeno-associated virus (rAAV) vector, to provide substrate for mitochondrial oxidative phosphorylation, thereby augmenting energetic metabolism and promoting cell and motor neuron survival.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If current FDA-approved treatments (Riluzole, Edaravone) are used, then disease progression is slowed, but no cure is available and survival remains limited to 2-4 years
Solution Approach 1:
The patent introduces ASPA enzyme as an intermediary substance that catalyzes the conversion of NAA to aspartate and acetate. This intermediary mechanism addresses the root metabolic dysfunction in ALS by replenishing aspartate pools, thereby improving mitochondrial function and extending survival beyond the limited 2-4 year prognosis of current treatments
Solution Approach 2:
The patent changes the metabolic parameter of aspartate concentration in motor neurons by introducing ASPA enzyme activity. This parameter change restores the malate-aspartate shuttle function, enabling efficient NADH oxidation and ATP production, thereby transforming the disease trajectory from progressive decline to potential reversal
2Reliability
If mitochondrial function is enhanced through ASPA overexpression, then ATP synthesis increases and cell survival improves, but the complexity of gene therapy delivery increases
Solution Approach 1:
The patent uses adeno-associated virus (AAV) as an intermediary delivery vehicle to transport the ASPA gene into motor neurons. This viral vector intermediary simplifies the complex process of gene delivery by leveraging natural viral mechanisms for efficient cellular uptake and sustained gene expression
Solution Approach 2:
The ASPA enzyme performs self-service by automatically catalyzing the conversion of endogenous NAA to aspartate within the cell. Once delivered via gene therapy, the enzyme autonomously maintains aspartate levels and supports mitochondrial function without requiring external intervention or complex delivery systems
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 method enhances mitochondrial function, increases ATP synthesis, and extends life expectancy by improving motor function and reducing symptoms in ALS patients, including those with specific genetic mutations.
Implementation Method 1
The method comprises introducing the nucleic acid to at least one cell of the subject by viral transduction
Implementation Method 2
increases intracellular activity of aspartoacylase (ASPA) in affected cell populations for the purpose of providing aspartate, a rate-limiting component of the malate-aspartate shuttle that provides affected cells with the ability to utilize cytosolic NADH to fuel mitochondrial oxidative phosphorylation
Implementation Method 3
providing substrate for mitochondrial oxidative phosphorylation
Implementation Method 4
aspartate, a rate-limiting component of the malate-aspartate shuttle that provides affected cells with the ability to utilize cytosolic NADH to fuel mitochondrial oxidative phosphorylation
Implementation Method 5
fuel mitochondrial oxidative phosphorylation
Implementation Method 6
increases ATP synthesis
Data Source
AI summary
This disclosure provides methods for treating, ameliorating, or reversing at least one symptom of amyotrophic lateral sclerosis (ALS) in a subject by increasing the amount of neuronal aspartate in spinal cord through administration of a therapeutically effective amount of a composition comprising a nucleic acid encoding ASPA or a functional fragment thereof.