The development of therapies for rare diseases (RDs) continues to face persistent challenges, including small and geographically dispersed patient populations, pronounced clinical heterogeneity, and the absence of standardized outcome measures. Basket trials—master protocol studies evaluating a single therapeutic intervention across multiple diseases linked by shared molecular or clinical characteristics—offer a promising solution to these constraints. This systematic review identified 36 basket trials targeting RDs through comprehensive searches of clinical trial registries, academic databases, and grey literature. The majority (75%) focused on rare oncological indications, with only nine trials addressing non-oncological RDs. These non-oncological studies were highly heterogeneous, spread across 25 distinct conditions without overlap, and faced persistent challenges such as the lack of validated biomarkers and standardized endpoints. Most studies (81%) were Phase II trials, highlighting the exploratory role of basket designs in early-stage development. Trial designs were predominantly non-randomized and open-label (86%), reflecting the practical limitations of implementing rigorous methodologies in small, heterogeneous populations. The average trial duration was 6.5 years, and recruitment was logistically demanding, with trials involving a mean of 56 sites and, in some cases, over 1,000 centers. While basket trials show clear potential to accelerate therapeutic innovation in RDs, their application remains limited beyond oncology. Methodological constraints—such as inconsistent endpoints, limited randomization, and underpowered subgroup analyses—continue to restrict their broader use. Enhancing the utility of basket trials will require greater regulatory flexibility, wider adoption of adaptive and Bayesian designs, integration of real-world evidence, and stronger engagement with patients and advocacy groups. This review underscores both the opportunities and limitations of basket trials in RDs and provides a roadmap for realizing their potential, calling for concerted efforts from regulators, researchers, and patient advocates to expand their application and impact across the RDs spectrum.
Myotonic dystrophy type I (DM1) is caused by CTG repeat expansions in the DMPK gene leading to mRNA toxicity and sequestration of the splicing regulator MBNL1, affecting many tissues. We have developed an in vitro screening platform based on ddPCR and in-cell western to quantify these mRNAs and proteins and characterized >20 cell models to define DM1 biomarkers that could be useful for drug screening. DMPK protein levels were reduced in DM1-immortalized myoblasts and myotubes, but not in fibroblasts, while MBNL1 protein was consistently lower in all DM1 myogenic cultures, whether primary or immortalized. Myogenic differentiation of cultures led to an increase in DMPK mRNA expression, which was translated into increased MBNL1 sequestration in foci. We further corroborated the platform's ability to assess therapeutic outcomes, evaluating the effect of a DMPK gapmer ASO and one siRNA: while the gapmer increased MBNL1 protein levels, the siRNA had no significant effect on MBNL1 release. Our platform and the in-depth characterization of some of the most used models would be of use to the DM1 research community.
Einleitung: Die Brentuximab Vedotin (BV) vermittelte Antikörper (AK)-Behandlung (CD30) ist zur Rezidivtherapie nach autologer Stammzelltransplantation (ASCT) für das Hodgkin Lymphom (HG) zugelassen. 2/3 der Patienten entwickeln hierbei eine reversible periphere Neuropathie (PN). Myositis als mögliche NW wurde bisher nicht berichtet.
