Grant Award Details
Targeted Gene Editing in the Treatment of X-Linked Hyper-IgM Syndrome
Hyper IgM Syndrome
<p><span style='color: rgb(0, 0, 0); font-family: "Roboto Slab", serif; font-size: 13.2px; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: rgb(255, 255, 255); text-decoration-style: initial; text-decoration-color: initial; display: inline !important; float: none;'>There is currently no curative treatment option for patients with a rare immunodeficiency called X-Linked Hyper-IgM syndrome (XHIM) if they do not have a bone marrow match or if they have been diagnosed with comorbidities that make stem cell transplant too risky. Even with a match, stem cell transplants have significant immunologic risks. This is also true for patients affected by other primary immune deficiencies and blood disorders. However, gene modified hematopoietic stem cells where the specific gene mutation is corrected can cure XHIM can provide a new therapeutic option for these patients. During this research proposal, we have identified a way to correct any mutation at the gene responsible for XHIM (called CD40 Ligand, or <em>CD40L</em>) using a gene editing technology called CRISPR/Cas9. The CRISPR/Cas9 system creates a targeted break in the DNA at the beginning of the <em>CD40L</em> gene; at around the same time this break occurs, a corrective DNA sequence that encodes a normal copy of the CD40L gene is introduced. This corrective CD40L gene sequence can then be inserted at the site of the CRISPR/Cas9 break in the DNA. This allows the gene to be fixed and remain under control of natural elements surrounding the gene that tell it when to turn on and off. Since this technology has high efficiency in bone marrow stem cells, XHIM patients can potentially be treated if their bone marrow is harvested, the CD40L gene is fixed in the lab, and their own, now corrected, bone marrow is returned to them. This eliminates any risk of rejection and requires lower loses of chemotherapeutic drugs needed for bone marrow conditioning. If gene corrected stem cells engraft successfully, these stem cells will give rise to normal T cells that can restore immune function.</span></p>
Grant Application Details
- Targeted Gene Editing in the Treatment of X-Linked Hyper-IgM Syndrome
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.
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.
Source URL: https://www.cirm.ca.gov/our-progress/awards/targeted-gene-editing-treatment-x-linked-hyper-igm-syndrome