Annemieke Aartsma-Rus, Rob W.J. Collin, Ype Elgersma, Marlen C. Lauffer, Willeke van Roon-Mom (Therapeutic Advances in Rare Disease)
September 23, 2024
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.
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.
Aartsma-Rus A, Collin RWJ, Elgersma Y, Lauffer MC, van Roon-Mom W. Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics. Therapeutic Advances in Rare Disease. 2024;5. doi:10.1177/26330040241273465
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