Gene-Edited HSPCs for Progranulin Delivery in Neurodegenerative Disease
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Solution Overview
Problem
Current treatments for frontotemporal dementia (FTD) are ineffective, and there is a need for new approaches to address neurodegenerative diseases mediated by progranulin deficiencies, as existing therapies fail to slow disease progression or provide a cure.
Innovation Solution
Genetically modified hematopoietic stem and progenitor cells (HSPCs) are used to express functional progranulin, either through CRISPR/Cas gene editing or viral vector transduction, which are administered to patients to enhance progranulin expression above endogenous levels, targeting neurodegenerative diseases such as FTD, ALS, Alzheimer's, and Parkinson's.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for frontotemporal dementia, then existing therapies are administered, but they fail to slow disease progression or provide a cure
Solution Approach 1:
The patent applies preliminary action by genetically modifying hematopoietic stem and progenitor cells ex vivo before administration to patients. The cells are pre-loaded with functional progranulin gene copies through CRISPR/Cas editing or viral vector transduction, so that when transplanted, they immediately begin producing therapeutic progranulin protein in the CNS, proactively addressing the deficiency before it can cause further damage.
Solution Approach 2:
The patent implements self-service through the use of autologous HSPCs that are harvested from the patient's own bone marrow, genetically modified to express functional progranulin, and then reinfused. The modified cells serve themselves by continuously producing and secreting progranulin protein, which is then taken up by microglia and neurons in the CNS, creating a self-sustaining therapeutic system that does not require repeated administrations.
2Duration of action of moving object
If genetically modified HSPCs are administered to enhance progranulin expression, then long-lasting delivery of therapeutic proteins is achieved, but the complexity of gene therapy approaches increases
Solution Approach 1:
The patent applies segmentation by dividing the therapeutic approach into distinct modular components: (1) HSPC isolation and culture, (2) genetic modification using either CRISPR/Cas gene editing or viral vector transduction, (3) ex vivo expansion and quality control, and (4) reinfusion. This modular segmentation allows each step to be optimized independently and facilitates regulatory approval while achieving long-lasting therapeutic effects.
Solution Approach 2:
The patent uses intermediaries in the form of viral vectors (such as lentiviral vectors) or CRISPR/Cas gene editing machinery as mediators to deliver the functional progranulin gene into the HSPCs. These intermediaries facilitate efficient genetic modification while maintaining cell viability, and the modified cells then serve as living factories that continuously produce therapeutic progranulin protein for extended periods.
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 approach enables long-lasting delivery of therapeutic proteins to the CNS, potentially slowing disease progression and improving symptoms by repopulating microglia capable of producing progranulin, thereby addressing the underlying pathophysiology of FTD and other neurodegenerative diseases.
Implementation Method 1
Genetically modified hematopoietic stem and progenitor cells (HSPCs) are used to express functional progranulin, either through CRISPR/Cas gene editing or viral vector transduction
Implementation Method 2
Genetically modified hematopoietic stem and progenitor cells (HSPCs) are used to express functional progranulin, either through CRISPR/Cas gene editing or viral vector transduction
Implementation Method 3
The approach enables long-lasting delivery of therapeutic proteins to the CNS, potentially slowing disease progression and improving symptoms by repopulating microglia capable of producing progranulin
Data Source
AI summary
The invention relates to the field of gene therapy and more specifically to hematopoietic stem and progenitor cells that have been genetically modified to express functional progranulin. Suitably, HSPCs that have gene edited using CRISPR/Cas technology, or have been transduced with lentiviral gene delivery vehicles. The invention also relates to the use of such modified HSPCs in therapy. In particular, the invention relates to use of the modified progranulin expressing HSPCs in the prevention or treatment of a neurodegenerative disease mediated by dysfunctional progranulin expression, such as frontotemporal dementia (FTD).