A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept In vivo Studies (excluding Non-Human Primates)
273: Optimizing Base Editing Strategies in a Mouse Model of Zellweger Syndrome
Type: Oral Abstract Session
Presentation Details
Session Title: AAV Vectors - Preclinical and Proof-of-Concept In vivo Studies II
Location: Room 408 AB
Start Time: 5/19/2023 16:30
End Time: 5/19/2023 16:45
Zellweger Syndrome is a rare disease associated with impaired peroxisome biogenesis and dysfunction caused by mutations in one of 13 genes responsible for peroxisome assembly. Peroxisomes play an important role in a number of cellular functions, including fatty acid metabolism, the catabolism of amino acids, and lipid biosynthesis. The spectrum of Zellweger disorder ranges from mild to severe, affecting a range of organ and tissue function. Patients typically present in early infancy with an incidence of 1 in 50,000 live births in the United States. Symptoms typically includes hypotonia, seizures, vision and hearing loss, as well as life threatening deficits in major organs. Mutations in the gene PEX1 account for the majority of Zellweger patients and the G843D mutation is one of the most common pathogenic variants. Mouse models have been engineered for a number of Zellweger causative genetic mutations including loss of function alleles and the murine equivalent of the G843D allele in the Pex1 gene. This mouse model displays many of the key features of Zellweger syndrome, including the accumulation of long chain fatty acids. Precision gene editing methods such as base editing and prime editing are promising technologies for the treatment of genetic diseases. Establishing methods for the in vivo delivery of new adenine base editors (ABEs) in animal models of human disease is a critical first step before assessing its therapeutic potential. The Liu group has developed therapeutically relevant delivery strategies for base editors in vivo, including single-AAV and dual-AAV approaches. Our preliminary data using adenine base editor ABE7.10max (ABEmax) suggest that the dual AAV system can correct Pex1 G844D mutation in vivo. To obtain higher correction levels, we applied recently evolved ABE8e and ABE8e-V106W, which are more active than ABEmax. These high-activity base editors resulted in a high degree of genome correction with few detected off-target affects. Preclinical efficacy testing in our mouse model resulted in a significant reduction in the levels of very long-chain fatty acid accumulation as well as lipid levels in the liver. These data demonstrate a promising approach for therapeutic base editing as a potential treatment for Zellweger Syndrome.
Cathleen Lutz1, Daniel Gao2, Maximiliano F. Presa3, Aamir Zuberi3, Samagya Banskota2, Joseph G. Hacia4, David R. Liu5
1Rare Disease Translational Center, The Jackson Laboratory, Bar Harbor, ME,2Broad Institute, Cambridge, MA,3The Jackson Laboratory, Bar Harbor, ME,4University of Southern California, Los Angeles, CA,5Harvard University and HHMI, Cambridge, MA
C. Lutz: None.
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