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

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.

Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies.

Preclinical animal studies are performed to analyse the safety and efficacy of new treatments, with the aim to protect humans. However, there are questions and concerns about the quality and usefulness of preclinical animal research. Translational success rates vary between 0 and 100%, and no clear relationship has been found with possible predictive factors such as animal species or field of research. Therefore, it is not yet possible to indicate what factors predict successful translation. Translational strategies were therefore discussed at an international conference held in the Netherlands in November 2019, aiming to develop practical guidelines for more robust animal-to-human translation. The conference was organised during the course of a research project funded by the Dutch Research Council (313-99-310), addressing possible solutions for the low translational values that had been published for a multitude of animal studies in human health care. This article provides an overview of the project and the conference discussions. Based on the conference results and the findings from the research project, we define four points of attention that are crucial in the search for improved translational success rates: (a) optimising the methods and design of studies; (b) incorporation of the complexity of the human patient in research; (c) start with the patient rather than existing animal models as the gold standard; and (d) more and better collaboration within the chain from funding to pharmacy. We conclude that this requires improved organization and use of procedures, as well as a change of attitude and culture in research, including a consideration of the translational value of animal-free innovations and human-relevant science.

A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies.

Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies.