Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations

Abstract

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.

Keywords: Europe; N = 1; antisense oligonucleotides; regulators; treatment.

FIGURE 1.

Approaches to tackle different genetic variants with splice-modulating ASOs. (Top panel) Nonsense variants and indels can lead to the generation of an early stop codon (disruption of open reading frame) within the transcript, and no functional protein being produced. ASO-mediated exon skipping can be used to restore the reading frame and results in the production of a truncated protein with (partial) function. (Middle panel) Toxic gain-of-function variants lead to the production of toxic proteins. ASOs can be used to skip exons to result in a shorter, nontoxic protein. (Bottom panel) Deep intronic variants can result in parts of the intron being included in the mRNA transcript, causing a shift in the reading frame and abolishing protein function. This intron integration can be prevented using ASOs leading to the canonical transcript being expressed and a restoration of the reading frame. (ASO) Antisense oligonucleotide.

FIGURE 2.

1M1M proposed options for capturing change in an n-of-1 treatment setting. To allow detection of change, a subject's disease course under treatment can be compared: (#1) intraindividually to the slope of his/her own run-in natural history disease course prior to treatment (see scenario #1); (#2) interindividually to a cohort of (historical or concurrent) disease controls (see scenario #2); or (#3) interindividually to healthy control reference ranges, for example, reference percentiles (see scenario #3).