Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy
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 transferri...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.154142 |
| _version_ | 1797634396287664128 |
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| author | Suzan M. Hammond Frank Abendroth Larissa Goli Jessica Stoodley Matthew Burrell George Thom Ian Gurrell Nina Ahlskog Michael J. Gait Matthew J.A. Wood Carl I. Webster |
| author_facet | Suzan M. Hammond Frank Abendroth Larissa Goli Jessica Stoodley Matthew Burrell George Thom Ian Gurrell Nina Ahlskog Michael J. Gait Matthew J.A. Wood Carl I. Webster |
| author_sort | Suzan M. Hammond |
| collection | DOAJ |
| description | 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, 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 that modulate splicing of the survival motor neuron 2 (SMN2) gene. Administration of 8D3130-ASO conjugate resulted in elevated levels of bioavailability to the brain. Additionally, 8D3130-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. |
| first_indexed | 2024-03-11T12:07:07Z |
| format | Article |
| id | doaj.art-e10b5264221549b9be42dfc52acf597f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:07Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-e10b5264221549b9be42dfc52acf597f2023-11-07T16:24:58ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-12-01724Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophySuzan M. HammondFrank AbendrothLarissa GoliJessica StoodleyMatthew BurrellGeorge ThomIan GurrellNina AhlskogMichael J. GaitMatthew J.A. WoodCarl I. WebsterAntisense 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, 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 that modulate splicing of the survival motor neuron 2 (SMN2) gene. Administration of 8D3130-ASO conjugate resulted in elevated levels of bioavailability to the brain. Additionally, 8D3130-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.https://doi.org/10.1172/jci.insight.154142Neuroscience |
| spellingShingle | Suzan M. Hammond Frank Abendroth Larissa Goli Jessica Stoodley Matthew Burrell George Thom Ian Gurrell Nina Ahlskog Michael J. Gait Matthew J.A. Wood Carl I. Webster Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy JCI Insight Neuroscience |
| title | Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy |
| title_full | Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy |
| title_fullStr | Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy |
| title_full_unstemmed | Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy |
| title_short | Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy |
| title_sort | antibody oligonucleotide conjugate achieves cns delivery in animal models for spinal muscular atrophy |
| topic | Neuroscience |
| url | https://doi.org/10.1172/jci.insight.154142 |
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