Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease
Precision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to ac...
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MDPI AG
2024-03-01
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| author | Nuria Suárez-Herrera Catherina H. Z. Li Nico Leijsten Dyah W. Karjosukarso Zelia Corradi Femke Bukkems Lonneke Duijkers Frans P. M. Cremers Carel B. Hoyng Alejandro Garanto Rob W. J. Collin |
| author_facet | Nuria Suárez-Herrera Catherina H. Z. Li Nico Leijsten Dyah W. Karjosukarso Zelia Corradi Femke Bukkems Lonneke Duijkers Frans P. M. Cremers Carel B. Hoyng Alejandro Garanto Rob W. J. Collin |
| author_sort | Nuria Suárez-Herrera |
| collection | DOAJ |
| description | Precision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to accelerate customized therapy design for rare cases. A strong candidate for this approach is Stargardt disease (STGD1), an autosomal recessive macular degeneration characterized by high genetic and phenotypic heterogeneity. STGD1 is caused by pathogenic variants in <i>ABCA4</i>, and amongst them, several deep-intronic variants alter the pre-mRNA splicing process, generally resulting in the insertion of pseudoexons (PEs) into the final transcript. In this study, we describe a 10-year-old girl harboring the unique deep-intronic <i>ABCA4</i> variant c.6817-713A>G. Clinically, she presents with typical early-onset STGD1 with a high disease symmetry between her two eyes. Molecularly, we designed antisense oligonucleotides (AONs) to block the produced PE insertion. Splicing rescue was assessed in three different in vitro models: HEK293T cells, fibroblasts, and photoreceptor precursor cells, the last two being derived from the patient. Overall, our research is intended to serve as the basis for a personalized N-of-1 AON-based treatment to stop early vision loss in this patient. |
| first_indexed | 2024-04-24T10:47:52Z |
| format | Article |
| id | doaj.art-78195cd5174e462d99f4bd1b2718bd4e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-24T10:47:52Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-78195cd5174e462d99f4bd1b2718bd4e2024-04-12T13:16:30ZengMDPI AGCells2073-44092024-03-0113760110.3390/cells13070601Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt DiseaseNuria Suárez-Herrera0Catherina H. Z. Li1Nico Leijsten2Dyah W. Karjosukarso3Zelia Corradi4Femke Bukkems5Lonneke Duijkers6Frans P. M. Cremers7Carel B. Hoyng8Alejandro Garanto9Rob W. J. Collin10Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsPrecision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to accelerate customized therapy design for rare cases. A strong candidate for this approach is Stargardt disease (STGD1), an autosomal recessive macular degeneration characterized by high genetic and phenotypic heterogeneity. STGD1 is caused by pathogenic variants in <i>ABCA4</i>, and amongst them, several deep-intronic variants alter the pre-mRNA splicing process, generally resulting in the insertion of pseudoexons (PEs) into the final transcript. In this study, we describe a 10-year-old girl harboring the unique deep-intronic <i>ABCA4</i> variant c.6817-713A>G. Clinically, she presents with typical early-onset STGD1 with a high disease symmetry between her two eyes. Molecularly, we designed antisense oligonucleotides (AONs) to block the produced PE insertion. Splicing rescue was assessed in three different in vitro models: HEK293T cells, fibroblasts, and photoreceptor precursor cells, the last two being derived from the patient. Overall, our research is intended to serve as the basis for a personalized N-of-1 AON-based treatment to stop early vision loss in this patient.https://www.mdpi.com/2073-4409/13/7/601N-of-1antisense oligonucleotidesplicing modulationpseudoexonRNA therapy<i>ABCA4</i> |
| spellingShingle | Nuria Suárez-Herrera Catherina H. Z. Li Nico Leijsten Dyah W. Karjosukarso Zelia Corradi Femke Bukkems Lonneke Duijkers Frans P. M. Cremers Carel B. Hoyng Alejandro Garanto Rob W. J. Collin Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease Cells N-of-1 antisense oligonucleotide splicing modulation pseudoexon RNA therapy <i>ABCA4</i> |
| title | Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease |
| title_full | Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease |
| title_fullStr | Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease |
| title_full_unstemmed | Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease |
| title_short | Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare <i>ABCA4</i> Variant in a Child with Early-Onset Stargardt Disease |
| title_sort | preclinical development of antisense oligonucleotides to rescue aberrant splicing caused by an ultrarare i abca4 i variant in a child with early onset stargardt disease |
| topic | N-of-1 antisense oligonucleotide splicing modulation pseudoexon RNA therapy <i>ABCA4</i> |
| url | https://www.mdpi.com/2073-4409/13/7/601 |
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