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 regards 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.

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

“…To properly define clinical outcome measures and assess treatment effects, sufficient clinical information regarding the individuals' phenotypes and the course of the disease is necessary [19]. However, information regarding the natural history and progression of rare disorders is limited and often incomplete simply on the basis of scarce accounts.…”

“…To successfully develop an ASO-based, diseasemodifying treatment, several steps need to be taken, such as (i) deciding which ASO approach is most suitable for the disorder in question, (ii) selecting eligible candidates for individualized treatments, (iii) defining clinical outcome measures, and (iv) setting up preclinical assays with functional readouts. Recommendations for deciding on the appropriate treatment strategy and prioritisation of eligible pathogenic variants have already been addressed by our group [16,17], and guidelines on preclinical testing of ASOs have been established together with our group [18,19].…”

Applying Lessons Learned from Developing Exon Skipping for Duchenne to Developing Individualized Exon Skipping Therapy for Patients with Neurodegenerative Diseases

“…31 Furthermore, the DCRT has produced educational papers in collaboration with N1C on which ASO modality apply to which genetic disease, 22 including also considerations and caveats, as well as guidance on preclinical assessment of efficiency for exon skipping ASOs. 32,33 The 1M1M network has produced a guidance document on eligibility criteria from a genetic, clinical, and ethical perspective. 34 Notably, in Europe individualized treatment can be done in a named patient setting and does not need approval from the European Medicines Agency (EMA), while in the USA an investigational new drug (IND) application has to be done to FDA even for individualized treatments.…”

“…), including also considerations and caveats, as well as guidance on preclinical assessment of efficiency for exon skipping ASOs. 26,27 The 1M1M network has produced a guidance document on eligibility criteria from a genetic, clinical and ethical perspective. 28 This example highlights several aspects.…”

Improved Prediction of Antisense Oligonucleotide Efficacy for Exon Skipping Using Ensemble Learning and Feature Selection

“…Milasen, a patient-customized n-of-1 ASO drug targeted for a pseudoexon in the CLN7 gene, was recently approved by the FDA for the treatment of Batten's Disease, demonstrating the potential of exon skipping for personalized medicine [14,15]. Exon skipping therapies are also being explored for other genetic diseases such as cystic fibrosis, retinitis pigmentosa, sarcoglycanopathy, dysferlinopathy, fibrodysplasia ossificans progressiva, epidermolysis bullosa, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and cancer, among others [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34].…”