The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

Data from: Differential introgression and reorganization of retrotransposons in hybrid zones between wild wheats

The maintenance of species integrity despite pervasive hybridization is ruled by the interplay between reproductive barriers. Endogenous postzygotic isolation will shape the patterns of introgression in hybrid zones, leading to variable outcomes depending on the genetic mechanism involved. Here, we analysed experimental and natural hybrid populations of Aegilops geniculata and Aegilops triuncialis to examine the genetics of species boundaries in the face of gene flow. Because long-terminal repeat retrotransposons (LTR-RTs) showing differential evolutionary trajectories are probably to affect hybrid dysgenesis and reproductive isolation between these wild wheat species, we addressed the impact of LTR-RTs in shaping introgression between them. Experimental settings involving artificial sympatry and enforced crossings quantified strong, but incomplete reproductive isolation, and highlighted asymmetrical endogenous postzygotic isolation between the two species. Natural hybrid zones located in the northern Golan Heights were analysed using plastid DNA, amplified fragment length polymorphisms (AFLP) marking random sequences, and sequence-specific amplified polymorphisms (SSAP) tracking insertions from six LTR-RT families. This analysis demonstrated asymmetrical introgression and genome reorganization. In comparison with random sequences and quiescent LTR-RTs, those LTR-RTs predicted to be activated following conflicting interactions in hybrids revealed differential introgression across the hybrid zones. As also reported for synthetic F1 hybrids, such LTR-RTs were specifically reorganized in the genomes of viable hybrids, confirming that conflicts between selfish LTR-RTs may represent key incompatibilities shaping species boundaries and fostering long-term species integrity in the face of gene flow

SampleCode

Code used to describe sampled individuals according to their population of origi

Whole genome duplications and recruitment of ecologically relevant genes in alpine Mustards

Polyploid taxa represent excellent models to address the underpinnings of genome evolution and the building up of new species in heterogeneous environments. Here, we present an overview of recent works in the alpine Biscutella laevigata autopolyploid complex (Brassicaceae). Transcriptomics inferred recurrent whole genome duplication (WGD) events specific to clade of species and that were used to infer processes fostering genome evolution across different timescales: (i) After a 7-8 million years old WGD event, intense chromosomal repatterning selected for clusters of retained duplicates enriched in functions associated with responses to abiotic stresses. Low coverage genome sequencing unraveled the dynamics of several retrotransposons, supporting interplay between genome reorganization and environmental opportunities in shaping the evolution of paleopolyploids. (ii) Retrotransposons in autotetraploids having recolonized the Alps after the ice ages showed considerable dynamics going along with ecological radiation following this recent WGD. Ecological genomics involving transplant experiment indeed supported distinct autopolyploid gene pools firmly associated with contrasted habitats despite gene flow. These ecotypes demonstrated adaptive differentiation at loci whose functions match habitat requirements. WGDs thus recurrently fostered genome reorganization and adaptive recruitment of genes responding to environmental factors, indicating that similar proximate and ultimate factors of genome dynamics may consistently act through time

Hybrdization_dataset

Raw data used to estimate spontaneous and artificial rates of hybridizatio

AFLP and SSAP Datasets

Contains binary scores for 3 AFLP combinations as well as 2 SSAP combinations for each family of retrotransposon (BARE1, Claudia, Egug, Fatima, Romani, Sabine). Details are provided on the first sheet of the Excell file

Alignment of plastid sequences

Alignment of plastid sequence