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Review
. 2024 Sep 23:5:26330040241273465.
doi: 10.1177/26330040241273465. eCollection 2024 Jan-Dec.

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics

Annemieke Aartsma-Rus  1 , Rob W J Collin  2 , Ype Elgersma  3 , Marlen C Lauffer  4 , Willeke van Roon-Mom  4
Affiliations
Review

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics

Annemieke Aartsma-Rus et al. Ther Adv Rare Dis. .

Abstract

Antisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability of each ASO ranges from thousands of patients worldwide to single individuals based on the prevalence of the causative pathogenic variant. It was shown that development of individualized ASOs was feasible within an academic setting, starting with Milasen for the treatment of a patient with CLN7 Batten's disease in the USA. Inspired by this, the Dutch Center for RNA Therapeutics (DCRT) was established by three academic medical centers in the Netherlands with a track record in ASO development for progressive, genetic neurodegenerative, neurodevelopmental, and retinal disorders. The goal of the DCRT is to bundle expertise and address national ethical, regulatory, and financial issues related to ASO treatment, and ultimately to develop individualized ASOs for eligible patients with genetic diseases affecting the central nervous system in an academic, not-for-profit setting. In this perspective, we describe the establishment of the DCRT in 2020 and the achievements so far, with a specific focus on lessons learned: the need for processes and procedures, the need for global collaboration, the need to raise awareness, and the fact that N-of-1 is N-of-a-few.

Keywords: N-of-1; RNA therapy; antisense oligonucleotide; individualized treatment.

Plain language summary

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics Many rare diseases have a genetic cause. Antisense oligonucleotides (ASOs) are short pieces of modified DNA that have therapeutic potential for some patients with rare diseases. However, often this is in a patient-specific setting, meaning individualized therapy development is required, which has little commercial opportunity for pharmaceutical companies. It was shown however that individualized ASOs can be developed by academics, starting with Milasen, which was developed for a unique DNA variant found in a child with Batten’s disease in the USA. Following in the footstep of these academic pioneers we established the Dutch Center for RNA Therapeutics (DCRT), which aims to develop individualized ASOs for eligible patients with eye or brain diseases in a not-for-profit setting. Our goal is to bundle expertise and address national, ethical, regulatory and financial issues related to individualized ASO development. In this perspective review we outline the achievements since establishing the DCRT in 2020, with a focus on lessons learnt along the way: the need for processes and procedures, the need for global collaboration, the need to raise awareness and the fact that very often ASOs developed for a single person, could be applied also to a few other patients with the same DNA variants.

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Conflict of interest statement

AAR, WvRM, YE and MCL: none related to this work. RWJC: none related to this work. For full transparency, RWJC is founder, shareholder of Astherna B.V., a startup company that develops RNA therapies to fight blindness. Astherna has licensed IP from Radboudumc of which RWJC is inventor. AAR and MCL are Guest Editors for the Special Collection this article is published in and are authors of this paper. AAR and WvRM are also Editorial Board Member of Therapeutic Advances in Rare Disease; therefore, the peer-review process was managed by alternative members of the board and the submitting Editors had no involvement in the decision-making process.

Figures

Figure 1.
Figure 1.
Timeline and context for establishing the Dutch Center for RNA Therapeutics. Schematic depiction of key publications and occurrences for the development of exon skipping antisense oligonucleotides for muscle, eye, and brain disorders and for the development of individualized antisense oligonucleotides. Source: Belgrad et al., Synofzik et al., Lauffer et al. ASO, antisense oligonucleotide; SMA, spinal muscular atrophy.
See this image and copyright information in PMC

References

    1. Kuijper EC, Bergsma AJ, Pijnappel W, et al. Opportunities and challenges for antisense oligonucleotide therapies. J Inherit Metab Dis 2021; 44(1): 72–87. - PMC - PubMed
    1. Dominski Z, Kole R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci USA 1993; 90(18): 8673–8677. - PMC - PubMed
    1. Duan D, Goemans N, Takeda S, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers 2021; 7(1): 13. - PMC - PubMed
    1. Aartsma-Rus A, Fokkema I, Verschuuren J, et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 2009; 30(3): 293–299. - PubMed
    1. van Deutekom JC, Bremmer-Bout M, Janson AA, et al. Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum Mol Genet 2001; 10(15): 1547–54. - PubMed

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