In Utero Treatment of Duchenne Muscular Dystrophy with Non-viral Gene Editing
Grant Award Details
Grant Type:
Grant Number:
DISC2-14097
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$2,035,544
Status:
Active
Grant Application Details
Application Title:
In Utero Treatment of Duchenne Muscular Dystrophy with Non-viral Gene Editing
Public Abstract:
Research Objective
To develop a lipid nanoparticle/mRNA complex that can safely and efficiently edit muscle stem cells in utero, correct the dystrophin mutation, and develop a treatment for Duchenne muscular dystrophy
Impact
If successful, we will have developed an effective and low-cost treatment for Duchenne muscular dystrophy and a robust method to safely and efficiently edit muscle stem cells in utero
Major Proposed Activities
To develop a lipid nanoparticle/mRNA complex that can safely and efficiently edit muscle stem cells in utero, correct the dystrophin mutation, and develop a treatment for Duchenne muscular dystrophy
Impact
If successful, we will have developed an effective and low-cost treatment for Duchenne muscular dystrophy and a robust method to safely and efficiently edit muscle stem cells in utero
Major Proposed Activities
- Develop LNP formulations containing either M6P-cholesterol or folate-PEG-DSPE
Develop LNP formulations that can efficiently deliver mRNA to MuSCs and muscle fibers in Ai9 mice via in utero injection- Correction of the point mutation in the D2-mdx mouse MuSCs by LNP/mRNA complexes in vitro
- Correct the mutation in D2-mdx mice after in utero injection of base editor mRNA/LNP complexes
- Evaluate the editing efficiency and DMD phenotypic correction in D2-mdx mice after in utero base editing
- Correct the point mutation in human DMD patient cells with ABE(NRCH)-LNPs
Statement of Benefit to California:
Duchenne muscular dystrophy is a long-term degenerative disorder that involves extortionate medical expenses, amounting to an annual average cost of over $50,000 per patient. Since our proposed treatment consists of a low-cost, single injection, we predict significant improvements in health care costs and medical treatment plans with the potential to be accessible to low-income patients and patients in underdeveloped and underserved medical communities.
Publications
- Nat Nanotechnol (2024): Acid-degradable lipid nanoparticles enhance the delivery of mRNA. (PubMed: 39179796)
- Bioact Mater (2023): A bio-instructive parylene-based conformal coating suppresses thrombosis and intimal hyperplasia of implantable vascular devices. (PubMed: 37408799)
- Bioact Mater (2023): In utero delivery of mRNA to the heart, diaphragm and muscle with lipid nanoparticles. (PubMed: 36844366)
- ACS Nano (2024): Widespread Gene Editing in the Brain via In Utero Delivery of mRNA Using Acid-Degradable Lipid Nanoparticles. (PubMed: 39445691)
