Consensus Guidelines for the Design and In Vitro Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides

Nucleic Acid Therapeutics, vol. 33, pp. 17–25

Abstract

Antisense oligonucleotides (ASOs) can modulate pre-mRNA splicing. This offers therapeutic opportunities for numerous genetic diseases, often in a mutation-specific and sometimes even individual-specific manner. Developing therapeutic ASOs for as few as even a single patient has been shown feasible with the development of Milasen for an individual with Batten disease. Efforts to develop individualized ASOs for patients with different genetic diseases are ongoing globally. The N = 1 Collaborative (N1C) is an umbrella organization dedicated to supporting the nascent field of individualized medicine. N1C recently organized a workshop to discuss and advance standards for the rigorous design and testing of splice-switching ASOs. In this study, we present guidelines resulting from that meeting and the key recommendations: (1) dissemination of standardized experimental designs, (2) use of standardized reference ASOs, and (3) a commitment to data sharing and exchange.

Authors 8

1. Annemieke M Aartsma-Rus corresponding Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

   Dutch Center for RNA Therapeutics, the Netherlands

   N = 1 Collaborative

2. Alejandro Garanto

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Pediatrics and Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

   Dutch Center for RNA Therapeutics, the Netherlands

3. Willeke van Roon‐Mom Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

   Dutch Center for RNA Therapeutics, the Netherlands

4. Erin M. McConnell
   Affiliation as printed

   N = 1 Collaborative

5. Victoria Suslovitch

   Boston Children's Hospital

   Affiliation as printed

   Department of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA

   N = 1 Collaborative

6. Winston X. Yan
   Affiliation as printed

   N = 1 Collaborative

7. Jonathan K. Watts

   University of Massachusetts Chan Medical School

   Affiliation as printed

   RNA Therapeutics Institute, UMass Chan Medical School, Worcester, Massachusetts, USA

8. Timothy W. Yu

   Boston Children's Hospital · Harvard University

   Affiliation as printed

   Department of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA

   Harvard Medical School, Division of Genetics and Genomics, Boston, Massachusetts, USA

   N = 1 Collaborative