A summary of the progress made in the second period of BATCure is presented by work package.
New models: We made and studied further new models of CLN3, CLN6 and CLN7 disease, including human cells, yeast strains that modelled disease mutations, zebrafish and existing mouse models.
Pathway leads: We studied cells including those from the mouse disease models. We found alterations in multiple lysosomal enzymes and changes in the amounts and distribution of lipid molecules and in stress pathways. CLN3 was shown to be able to transport specific ions, and we were able to explain the cause of defects of other ion levels. The data for the gene network and the regulatory processes was deposited into an internal database for BATCure. We tested the promise of some lead compounds in cell models.
Metabolome: We found disturbances in the metabolism of several disease models.
Natural history: We confirmed that organs beyond the brain – such as the heart – are affected and should be considered as necessary targets for future experimental therapies. We also showed that MRIs can be a helpful way of measuring changes in the brain and that some medication can trigger a crisis.
Compound leads: We continued our testing of compound hits as well as new derivatives as part of Structure Activity Relationship modelling and their effect on pathways of interest. Multiple compounds were able to rescue phenotypes of yeast or cell models. These were assessed for their ability to reach the brain therefore potential to be used in treatments.
Zebrafish triage: Two compounds were shown to ameliorate phenotypes of a zebrafish model of CLN3 disease.
Gene therapy: Effective gene therapy vectors and protocols have been developed that allow the rescue of the retinal and brain pathology either completely or very substantially for the three mouse disease models, with concern over toxicology for one.
Drug therapy: In one mouse disease model we found alternations of several physiological amino acids in the brain. We found one of our hit molecules was protective in a mouse model, and another lead helped cell models.
Patient organisation involvement: An EU wide survey provided a forum for those affected by Batten disease to directly inform the work of BATCure and beyond, bringing the views of families to influence research and future clinical applications. We developed effective communication and dissemination over a range of media, in 10 major EU languages, that proved successful in raising awareness of the project, Batten disease and strengthened links within the NCL community.
Exploitation and dissemination:
IP has been produced that has the potential for commercial exploitation, subject to future funding to allow testing of potential therapeutic compounds in mouse models and provide the data required to launch clinical trials.
The dissemination aimed to maximise the outreach of the project in an appropriate and accessible form for relevant interested parties and the wider public.
The key audiences for BATCure were: the scientific community, NCL Professionals, patients & affected families, stakeholders, the wider public. The key dissemination channels and activities were: publications (including some reviews), presentations and attendance at scientific meeting and other related events, digital/online activities (website, social media), print including newsletter, flyers, posters, reports, press releases, audio (podcasts); laboratory open days, BDFA annual family conferences. Dissemination of the scientific results especially will continue beyond the end of the project.
