TY  - BOOK
AU  - Hammond,Suzan M.
AU  - Abendroth,Frank
AU  - Goli,Larissa
AU  - Stoodley,Jessica
AU  - Burrell,Matthew
AU  - Thom,George
AU  - Gurrell,Ian
AU  - Ahlskog,Nina
AU  - Gait,Michael J.
AU  - Wood,Matthew J.A.
AU  - Webster,Carl I.
TI  - Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy
PY  - 2022///-12-22
PB  - American Society for Clinical Investigation, 
KW  - Text
KW  - local
N1  - /pmc/articles/PMC7614086; /pubmed/36346674
N2  - Antisense oligonucleotides (ASOs) have emerged as one of the most innovative new genetic drug modalities. However, their high molecular weight limits their bioavailability for otherwise-treatable neurological disorders. We investigated conjugation of ASOs to an antibody against the murine transferrin receptor, 8D3(130), 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 that modulate splicing of the survival motor neuron 2 (SMN2) gene. Administration of 8D3(130)-ASO conjugate resulted in elevated levels of bioavailability to the brain. Additionally, 8D3(130)-ASO yielded therapeutic levels of SMN2 splicing in the central nervous system of adult human SMN2-transgenic (hSMN2-transgenic) mice, which resulted in extended survival of a severely affected SMA mouse model. Systemic delivery of nucleic acid therapies with brain-targeting antibodies offers powerful translational potential for future treatments of neuromuscular and neurodegenerative diseases
UR  - http://dx.doi.org/10.1172/jci.insight.154142
ER  -