Gene Therapy Compositions to Restore Glycogenolysis in GSD VI and IX
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Solution Overview
Problem
There are no disease-modifying therapies for Glycogen Storage Diseases (GSDs) like GSD VI and GSD IX, leading to impaired glycogenolysis, hepatomegaly, hypoglycemia, ketosis, growth retardation, and liver fibrosis, with current treatments only addressing symptoms rather than the underlying cause.
Innovation Solution
Administration of nucleic acid molecules and vectors encoding polypeptides that restore glycogen metabolic pathways, specifically targeting PhK subunit activity, to treat and prevent GSD VI and GSD IX by enhancing glycogenolysis and reducing glycogen accumulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current symptomatic treatments are used for GSD VI and GSD IX, then patient symptoms can be managed, but the underlying cause of the disease and disease progression cannot be addressed
Solution Approach 1:
The patent uses AAV vectors as intermediary carriers to deliver functional phosphoribosyltransferase gene copies into patient cells. The AAV vector acts as a mediator between the therapeutic gene and the target cells, enabling safe and efficient gene delivery without direct genetic manipulation of the patient's own genes.
Solution Approach 2:
The patent introduces a functional copy of the phosphoribosyltransferase gene to compensate for the defective endogenous gene. Instead of attempting to repair the original gene, the invention creates a backup copy that performs the necessary metabolic function, allowing the defective gene to remain unchanged while still achieving therapeutic effect.
2Reliability
If invasive procedures are used to address underlying disease causes, then definitive therapy can be achieved, but patient invasiveness and procedural risk increase
Solution Approach 1:
The patent replaces invasive mechanical surgical procedures with a non-invasive viral vector delivery system. Instead of using surgery or other invasive methods to deliver therapeutic genes, the invention uses AAV vectors that can be administered through less invasive routes such as intravenous injection, thereby reducing patient risk while achieving the same therapeutic goal.
Solution Approach 2:
The AAV vector serves as an intermediary that enables gene delivery without direct surgical intervention. The vector naturally infects and delivers genetic material to target cells, replacing the need for invasive surgical procedures that would otherwise be required to achieve definitive gene therapy.
3Quantity of substance
If glycogen breakdown is impaired in GSD VI and GSD IX, then glycogen accumulates in the liver, but this leads to hepatomegaly, liver fibrosis, and other sequelae
Solution Approach 1:
The patent enables the patient's own cells to restore their glycogen breakdown capability by introducing the functional phosphoribosyltransferase gene. The modified patient cells then self-correct the metabolic defect by producing the missing enzyme, which restores normal glycogenolysis and prevents glycogen accumulation without requiring continuous external intervention.
Solution Approach 2:
The patent changes the metabolic parameter of phosphoribosyltransferase enzyme activity in the patient's cells from deficient to sufficient levels. By introducing the functional gene, the enzyme activity parameter is restored to normal ranges, thereby correcting the underlying metabolic defect that causes glycogen accumulation and subsequent liver damage.
Data Source
AI summary
Glycogen storage disease (GSD) types VI and IX are caused by phosphorylase system deficiencies and these GSDs are often clinically indistinguishable from one another. Disclosed herein are compositions for and methods of treating and/or preventing GSD VI and GSD IX disease progression with gene therapy alone or in combination with other therapies.