Autologous HSPC Gene Therapy for Sustained Factor VIII Expression
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Solution Overview
Problem
Current treatments for bleeding disorders like haemophilia A and B, such as haemophilia A, are limited by the need for frequent injections, development of neutralizing antibodies, high cost, and limited accessibility, with viral vector therapies like AAV being ineffective in populations with pre-existing immunity.
Innovation Solution
A method involving the harvesting of autologous mobilized peripheral blood stem cells, enrichment of CD34+ cells, transduction with a lentiviral vector (CD68-ET3-LV) to express Factor VIII, and intravenous administration, combined with myeloablative or non-myeloablative conditioning for engraftment, to restore Factor VIII biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV-based gene therapy is used to deliver FVIII or FIX genes, then long-lasting expression can be achieved, but pre-existing immunity in 30-70% of the population excludes a large proportion of individuals from treatment
Solution Approach 1:
The patent changes the viral vector parameter from AAV to lentiviral vectors, which do not trigger pre-existing immunity responses. This parameter change allows the therapy to be applicable to the entire patient population including those with pre-existing AAV immunity, while maintaining long-lasting transgene expression through integration into host genome
2Reliability
If recombinant or plasma-derived clotting factors are administered frequently to maintain therapeutic levels, then bleeding episodes can be prevented, but the treatment becomes costly and inconvenient requiring frequent intravenous injections
Solution Approach 1:
The patent performs preliminary action by introducing the therapeutic gene into hematopoietic stem cells ex vivo before transplantation. The modified stem cells then continuously produce clotting factors in vivo, eliminating the need for frequent subsequent administrations and providing long-term therapeutic effect
3Adaptability or versatility
If protein-based replacement therapy is made accessible to more of the world population, then more patients can receive treatment, but the high cost limits accessibility to less than 30% of the global population
Solution Approach 1:
The patent implements self-service by enabling the patient's own stem cells to produce the therapeutic clotting factors continuously. This one-time gene modification creates a self-sustaining production system within the patient, eliminating ongoing purchase and administration costs of recombinant proteins
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 achieves sustained Factor VIII expression, reducing the frequency of treatments and minimizing the risk of inhibitor development, while being accessible and affordable, with improved engraftment and expression levels.
Implementation Method 1
transducing the enriched population of hematopoietic stem and progenitor cells with lentiviral vector such as CD68-ET3-LV or modifications thereof
Data Source
AI summary
Aspects of the present disclosure are directed to a gene therapy approach for treating bleeding disorders, in particular Haemophilia comprising transduction of autologous hematopoietic stem and progenitor cells (HSPCs) with lentiviral viral vectors for expression of blood clotting factors to correct their deficiency in these disorders. The invention further discloses a process and formulation comprising transduced cells for the administration to patients, preferably with bleeding disorders, in particular preceded by a conditioning regimen.The disclosure also describes myeloablative, non-myeloablative or non-genotoxic conditioning regimens, for preparing the patient for transplantation with formulation of the invention.