CRISPR-Cas9 Gene Editing for Hyper IgM Syndrome
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Solution Overview
Problem
Current treatments for Hyper-IgM Syndrome are inefficient, with about 80% of patients dying before the age of thirty, highlighting the need for novel therapeutic strategies to restore B cell class switching and improve immune function.
Innovation Solution
An adoptive immunotherapy approach using gene-corrected autologous T cells and hematopoietic stem/progenitor cells (HSPC) edited with a CRISPR/Cas system to restore functional CD40L expression, thereby promoting B cell class switching and enhancing immune function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments (immunoglobulin replacement therapy, antibiotics, antifungals, G-CSF) are used for HIGM patients, then patients receive standard care, but treatment efficiency is low with about 80% of patients dying before age thirty
Solution Approach 1:
The invention changes the fundamental parameter of treatment approach from symptomatic management (immunoglobulin replacement, antibiotics) to curative gene correction. By using CRISPR/Cas9 to correct the underlying CD40LG gene mutation in hematopoietic stem cells, the treatment addresses the root cause rather than just managing symptoms, thereby improving both survival rate and treatment efficiency
Solution Approach 2:
The invention introduces CRISPR/Cas9 gene editing technology as an intermediary mechanism to correct the defective CD40LG gene. This intermediary system enables precise genetic correction in hematopoietic stem cells, which then regenerate the immune system with functional CD40L expression, overcoming the limitations of conventional treatments
2Reliability
If adoptive immunotherapy with gene-corrected T cells is used, then B cell class switching is restored, but multiple administrations are required to reconstitute a broad T cell repertoire
Solution Approach 1:
The invention performs preliminary action by correcting the CD40LG gene in hematopoietic stem cells before immune system reconstitution. This upfront genetic correction in stem cells ensures that all subsequently generated T cells and other hematopoietic cells will express functional CD40L, eliminating the need for multiple repeated administrations and enabling long-lasting therapeutic benefit
Solution Approach 2:
The invention expands the gene editing strategy from correcting only T cells to correcting hematopoietic stem/progenitor cells, which give rise to multiple cell types including T cells, B cells, NK cells, monocytes, basophils, and eosinophils. This universal approach in stem cells provides broader and prolonged therapeutic benefit across the entire immune system rather than requiring cell-type-specific repeated treatments
3Reliability
If CRISPR/Cas9 gene editing is applied to correct CD40L gene mutations, then functional CD40L expression is restored, but precise editing of exons 2-5 is required to maintain proper gene function
Solution Approach 1:
The invention applies local quality by designing guide RNAs that specifically target only the mutated exons (exons 2-5) of the CD40LG gene while leaving other regions untouched. This localized editing approach ensures that corrections are made precisely where needed to restore function without introducing unintended changes to other parts of the gene or genome, maintaining proper gene function and expression
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 demonstrates high levels of CD40L gene editing and functional exogenous CD40L expression, leading to increased production of IgG and decreased production of IgM, providing therapeutic benefits for Hyper-IgM Syndrome.
Implementation Method 1
Recently, the CRISPR/Cas system has been adapted for genome editing in eukaryotic cells. The introduction of site-specific double strand breaks (DSBs) allows for target sequence alteration through endogenous DNA repair mechanisms
Implementation Method 2
The introduction of site-specific double strand breaks (DSBs) allows for target sequence alteration through endogenous DNA repair mechanisms
Implementation Method 3
RNA is transcribed from a portion of the CRISPR locus that includes the viral sequence. That RNA, which contains sequence complementary to the viral genome, mediates targeting of a Cas9 protein to a target sequence in the viral genome
Implementation Method 4
The Cas9 protein, in turn, cleaves and thereby silences the viral target
Implementation Method 5
The introduction of site-specific double strand breaks (DSBs) allows for target sequence alteration through endogenous DNA repair mechanisms, for example non-homologous end-joining (NHEJ) or homology-directed repair (HDR)
Implementation Method 6
The introduction of site-specific double strand breaks (DSBs) allows for target sequence alteration through endogenous DNA repair mechanisms, for example non-homologous end-joining (NHEJ) or homology-directed repair (HDR)
Data Source
AI summary
Disclosed herein are genome editing systems and related methods which allow for treatment of Hyper IgM Syndrome, a group of disorders characterized by defective CD40 signaling. The compositions and methods described herein rely on the use of donor templates comprising a CD40L exons to restore proper CD40 signaling and B cell class switch recombination.