The Department of Biological Sciences welcomes 

Dr. Michelle L. Hastings

Pfizer Upjohn Research Professor

Department of Pharmacology, University of Michigan Medical School

Splice-Switching Antisense Oligonucleotide Drug Discovery and Development for CLN3 Batten Disease

We have devised a therapeutic strategy for treating CLN3 Batten disease using splice-switching antisense oligonucleotides (ASO) that induce skipping of a targeted exon to partially correct gene expression that is disrupted by frame-shifting mutations. We have demonstrated the therapeutic potential of an ASO that partially corrects the CLN3deltaex7/8 (~ 1kb deletion), that is a common cause of the disease. The ASO effectively reduces neurological disease burden in mouse models when delivered to the central nervous system, and in reducing retinal dysfunction in a pig model of the disease, when delivered by intravitreal injection to the retina. This ASO is currently being advanced for clinical development. We leveraged these results to support the development of another ASO that targets a rare pathogenic variant,CLN3 c.569dupG in exon 8. We designed an approach to induce skipping of exon 8 using an ASO. We tested the ASO approach in cell and animal models and identified the lead ASO, Zebronkysen. After rigorous safety testing Zebronkysen received FDA approval for treatment in 14 year old twins with this rare pathogenic variant. A clinical protocol was developed with a dosing regimen based on non-clinical biodistribution and toxicity studies, safety monitoring based on ASO and disease-specific risks, biomarkers and outcome measures to track disease progression, tailored to each subject's status. To date, the children have been treated with five doses of Zebronkysen via lumbar puncture every three months, with dose escalation to a target of 45 mg. Zebronkysen has been well-tolerated, with no severe drug-related adverse events. During the first year there was no disease progression or loss of abilities, and improvements in several domains including motor function, mood, behavior and autonomic function. Together our results suggest that ASO-mediated exon skipping is an effective therapeutic approach for CLN3 Batten disease-causing variants. 

Hosted by Dr. Biological Sciences Graduate Students Association

This seminar will be streamed live. For a zoom link, please contact Dr. Eleni Gourgou at elenigourgou@wayne.edu.