The University of Michigan at Ann Arbor has received a USD 1.35 million NIH U01 grant to conduct IND-enabling studies for an antisense oligonucleotide (ASO) therapy targeting the most common genetic cause of CLN3 Batten disease, a fatal pediatric neurodegenerative disorder. The award, jointly funded by NINDS and NCATS, moves an exon-skipping approach toward a first-in-human trial.
CLN3 Batten disease is caused most often by a deletion spanning exons 7 and 8 of the CLN3 gene, producing a premature stop codon and loss of functional protein. The disorder leads to progressive vision loss, cognitive decline, seizures, and death, typically in the second or third decade of life. Principal investigator Michelle L. Hastings and collaborators previously developed an ASO, zebronkysen, that induces skipping of exon 8 in a different CLN3 variant; two treated children have shown reduced disease markers in cerebrospinal fluid. This new project applies the same exon-skipping logic to the more prevalent CLN3Δex7/8 deletion, using an ASO that skips exon 5 to restore a naturally occurring, functional protein isoform. Knock-in mouse and pig models carrying the mutation have shown reduced disease burden with this approach, according to the grant abstract. Funds will support toxicology and pharmacodynamic studies, drug manufacturing, and preparation of an Investigational New Drug application, with an initial trial planned in two affected children.
Batten disease has no approved disease-modifying therapy, and treatment options remain limited to symptom management. The project reflects a broader pattern of applying patient-specific or mutation-specific ASO strategies to ultra-rare pediatric neurodegenerative diseases, an approach also seen in milasen and other individualized ASO programs, though this effort aims for applicability across a larger subset of CLN3 patients rather than a single individual. The dual funding structure, combining NINDS's disease-specific mandate with NCATS's translational science focus, is consistent with NIH's increasing use of cross-institute mechanisms to move rare disease therapeutics from academic labs toward IND filings.
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