- [NATURE] A framework for individualized splice-switching oligonucleotide therapy
- 관리자 |
- 2024-07-03 16:18:21|
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- 2024-07-03 16:18:21|
[Title]
A framework for individualized splice-switching oligonucleotide therapy
[Author]
Jinkuk Kim1,2,3,4,19 ✉, Sijae Woo1,19, Claudio M. de Gusmao5,6,19, Boxun Zhao7,8,9,10,11,19, Diana H. Chin7, Renata L. DiDonato7, Minh A. Nguyen7, Tojo Nakayama7,11, Chunguang April Hu7, Aubrie Soucy7, Ashley Kuniholm12, Jennifer Karlin Thornton13, Olivia Riccardi7, Danielle A. Friedman5,7, Christelle Moufawad El Achkar5,11, Zane Dash7, Laura Cornelissen14, Carolina Donado14, Kamli N. W. Faour7, Lynn W. Bush7,9,15, Victoria Suslovitch7, Claudia Lentucci7, Peter J. Park16, Eunjung Alice Lee7,9,10,11, Al Patterson11,17, Anthony A. Philippakis18, Brad Margus13, Charles B. Berde11,14 & Timothy W. Yu7,8,9,10,11 ✉
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
3KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
4Center for Epidemic Preparedness, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
5Department of Neurology, Boston Children’s Hospital, Boston, MA, USA.
6Postgraduate School of Medical Science, University of Campinas (UNICAMP), São Paulo, Brazil.
7Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.
8Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA.
9Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA.
10Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
11Harvard Medical School, Boston, MA, USA.
12Institutional Center for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA.
13Ataxia Telangiectasia Children’s Project, Coconut Creek, FL, USA.
14Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA.
15Center for Bioethics, Harvard Medical School, Boston, MA, USA.
16Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
17Department of Pharmacy, Boston Children’s Hospital, Boston, MA, USA.
18Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
19These authors contributed equally: Jinkuk Kim, Sijae Woo, Claudio M. de Gusmao, Boxun Zhao. ✉e-mail: jinkuk@kaist.ac.kr; timothy.yu@childrens.harvard.edu
[Journal]
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.
A framework for individualized splice-switching oligonucleotide therapy
[Author]
Jinkuk Kim1,2,3,4,19 ✉, Sijae Woo1,19, Claudio M. de Gusmao5,6,19, Boxun Zhao7,8,9,10,11,19, Diana H. Chin7, Renata L. DiDonato7, Minh A. Nguyen7, Tojo Nakayama7,11, Chunguang April Hu7, Aubrie Soucy7, Ashley Kuniholm12, Jennifer Karlin Thornton13, Olivia Riccardi7, Danielle A. Friedman5,7, Christelle Moufawad El Achkar5,11, Zane Dash7, Laura Cornelissen14, Carolina Donado14, Kamli N. W. Faour7, Lynn W. Bush7,9,15, Victoria Suslovitch7, Claudia Lentucci7, Peter J. Park16, Eunjung Alice Lee7,9,10,11, Al Patterson11,17, Anthony A. Philippakis18, Brad Margus13, Charles B. Berde11,14 & Timothy W. Yu7,8,9,10,11 ✉
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
3KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
4Center for Epidemic Preparedness, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
5Department of Neurology, Boston Children’s Hospital, Boston, MA, USA.
6Postgraduate School of Medical Science, University of Campinas (UNICAMP), São Paulo, Brazil.
7Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.
8Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA.
9Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA.
10Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
11Harvard Medical School, Boston, MA, USA.
12Institutional Center for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA.
13Ataxia Telangiectasia Children’s Project, Coconut Creek, FL, USA.
14Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA.
15Center for Bioethics, Harvard Medical School, Boston, MA, USA.
16Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
17Department of Pharmacy, Boston Children’s Hospital, Boston, MA, USA.
18Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
19These authors contributed equally: Jinkuk Kim, Sijae Woo, Claudio M. de Gusmao, Boxun Zhao. ✉e-mail: jinkuk@kaist.ac.kr; timothy.yu@childrens.harvard.edu
[Journal]
Nature volume 619, pages828–836 (2023)
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.