PT  - JOURNAL ARTICLE
AU  - Suzan M Hammond
AU  - Frank Abendroth
AU  - Larissa Goli
AU  - Matthew Burrell
AU  - George Thom
AU  - Ian Gurrell
AU  - Jessica Stoodley
AU  - Nina Ahlskog
AU  - Michael J Gait
AU  - Matthew J A Wood
AU  - Carl Webster
TI  - Systemic antibody-oligonucleotide delivery to the central nervous system ameliorates mouse models of spinal muscular atrophy
AID  - 10.1101/2021.07.29.454272
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.29.454272
4099  - http://biorxiv.org/content/early/2021/07/29/2021.07.29.454272.short
4100  - http://biorxiv.org/content/early/2021/07/29/2021.07.29.454272.full
AB  - Antisense oligonucleotides (ASOs) have emerged as one of the most innovative new genetic drug modalities, however, the high molecular weight limits their bioavailability for otherwise treatable neurological disorders. We investigated conjugation of ASOs to an antibody against the murine transferrin receptor (TfR), 8D3130, and evaluated it via systemic administration in mouse models of the neurodegenerative disease, spinal muscular atrophy (SMA). SMA like several other neurological and neuromuscular diseases, is treatable with single-stranded ASOs, inducing splice modulation of the survival motor neuron 2 (SMN2) gene. Administration of 8D3130-ASO conjugate resulted in bioavailability of 2.7% of the injected dose in brain. Additionally, 8D3130-ASO yielded therapeutically high levels of SMN2 splicing in the central nervous system of mildly affected adult SMA mice and resulted in extended survival of severe SMA mice. Systemic delivery of nucleic acid therapies with brain targeting antibodies offers powerful translational potential for future treatments of neuromuscular and neurodegenerative diseases.Competing Interest StatementM.J.G. and M.J.A.W. are co-founders and equity holders in PepGen, a company developing peptide-conjugated oligonucleotides. C.W., M.B., G.T., and I.G., are employed by AstraZeneca. All other authors declare no competing interests.