Targeted Gene Editing in the Treatment of X-Linked Hyper-IgM Syndrome

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Grant Award Details

Grant Type:
Quest – Discovery Stage Research Projects
Grant Number:
DISC2-10124
Investigator(s):
Name:
Dr. Caroline Y. Kuo
Institution:
University of California, Los Angeles
Type:
PI

Disease Focus:
Blood Disorders, Hyper IgM Syndrome
Human Stem Cell Use:
Adult or Tissue Stem Cell
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

  • 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