Targeted Gene Editing in the Treatment of X-Linked Hyper-IgM Syndrome
Grant Award Details
Grant Type:
Grant Number:
DISC2-10124
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$1,512,333
Status:
Closed
Progress Reports
Reporting Period:
Year 2/NCE
Grant Application Details
Application Title:
Targeted Gene Editing in the Treatment of X-Linked Hyper-IgM Syndrome
Public Abstract:
Research Objective
We are seeking to develop site-specific hematopoietic stem cell gene therapy with autologous transplant as a definitive treatment option for X-linked Hyper-IgM Syndrome.
Impact
These studies would bring stem cell gene therapy for X-HIGM closer to the clinic, as there are currently no options for those without an HLA match or with infections too severe for allogeneic HSCT.
Major Proposed Activities
We are seeking to develop site-specific hematopoietic stem cell gene therapy with autologous transplant as a definitive treatment option for X-linked Hyper-IgM Syndrome.
Impact
These studies would bring stem cell gene therapy for X-HIGM closer to the clinic, as there are currently no options for those without an HLA match or with infections too severe for allogeneic HSCT.
Major Proposed Activities
- Identify the optimal CRISPR gRNA, Cas9 variant, and cDNA donor template targeting the CD40L gene.
- Compare TALENs and CRISPR/Cas9 targeting the CD40L gene in terms of their activity, specificity, and ability to allow homology-directed repair in CD34+ PBSC through short term cultures in vitro.
- Evaluate methods to maximize gene editing and maintain HSC survival and pluripotency.
- Evaluate the efficacy of optimized genome-editing reagents in hematopoietic stem cells long term in vitro in the artificial thymic organoid system and in vivo in NSG mice.
- Assess gene editing of the CD40L gene of X-HIGM patient derived CD34+ cells using the optimal gene editing platform and reagents determined in Milestones 1-4.
Statement of Benefit to California:
Safe, definitive therapies for X-HIGM represent an unmet medical need. Allogeneic stem cell transplant is frequently complicated by graft-versus-host disease and worsening of pre-existing infections. Successful demonstration that stem cell gene therapy can safely and effectively cure X-HIGM will shift the paradigm by which patients will be treated, led by California’s position as a leader in the field of gene therapy. This will result in improved patient care in the state and around the world.
Publications
- Cell Rep (2018): Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome. (PubMed: 29847792)
