TY  - JOUR
AU  - Synofzik, Matthis
AU  - van Roon-Mom, Willeke M C
AU  - Marckmann, Georg
AU  - van Duyvenvoorde, Hermine A
AU  - Graessner, Holm
AU  - Schüle, Rebecca
AU  - Aartsma-Rus, Annemieke
TI  - Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives.
JO  - Nucleic acid therapeutics
VL  - 32
IS  - 2
SN  - 1050-5261
CY  - New Rochelle, NY
PB  - Liebert
M1  - DZNE-2022-00621
SP  - 83 - 94
PY  - 2022
N1  - (CC BY)
AB  - Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on 'more common' RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.
KW  - Europe
KW  - Humans
KW  - Oligonucleotides
KW  - Oligonucleotides, Antisense: genetics
KW  - Oligonucleotides, Antisense: therapeutic use
KW  - antisense oligonucleotides (Other)
KW  - ethics (Other)
KW  - n-of-1 (Other)
KW  - policy (Other)
KW  - rare diseases (Other)
KW  - rare neurological diseases (Other)
KW  - regulatory (Other)
KW  - Oligonucleotides (NLM Chemicals)
KW  - Oligonucleotides, Antisense (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34591693
C2  - pmc:PMC9058873
DO  - DOI:10.1089/nat.2021.0039
UR  - https://pub.dzne.de/record/163947
ER  -