Oligonucleotide-Mediated Gene Repair

Thomas Rando, MD, PhD

Stanford University (Palo Alto, CA)

Dr. Rando is Associate Professor in the Department of Neurology at the Stanford University School of Medicine and Chief of Neurology at the Palo Alto VA Medical Center (Palo Alto, CA).

Past Projects

Test the potential of oligonucleotides to induce single base changes in the dysferlin gene to correct point mutations or alter splicing

LGMD2B is due to mutations in the dysferlin gene, some of which are point mutations resulting in stop codons. Previous studies have revealed the potential of small oligonucleotide vectors to induce single base changes in genomic DNA, thereby offering the possibility of therapeutic applications in diseases due to point mutations. This project explores the potential of custom-designed oligonucleotides to effect single base changes in the dysferlin gene in a mouse model of LGDM2B. Studies will be done on isolated muscle cells from those mice as well as directly on muscles in vivo. The effectiveness will be assessed by the restoration of dysferlin expression and by direct tests of gene correction.

Outcome: This project demonstrated correction of point mutations in dysferlin via use of oligonucleotides. The correction efficiency, however, was too low to be clinically useful unless substantial improvements in transfection efficiency can be made in the future.