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Developing new therapies for Batten disease

Periodic Reporting for period 2 - BATCure (Developing new therapies for Batten disease)

Reporting period: 2017-07-01 to 2019-06-30

The neuronal ceroid lipofuscinoses (NCL), commonly known as Batten disease, are the most common group of neurodegenerative disorders of children, affecting approximately 14,000 world-wide, with around 1,400 new cases each year. They are a devastating and severely debilitating group of genetic diseases. At the beginning of this project there were no established curative treatments offered in the clinic for any type of NCL anywhere in the world.

Families affected by all types of NCL are found throughout Europe, with the exact distribution of genetic sub-types varying from country to country. This project focused on developing treatments for three distinct diseases that account for more than half of all cases diagnosed with Batten disease and directly affect the lives of thousands of living children and adults. The incidence of CLN3 disease is highest in northern European countries. Exact figures for the rarest genetic types are not known, but the incidence of CLN6 or CLN7 disease mutations, the next most common transmembrane types, is highest in southern and Mediterranean Europe.

Batten disease mainly affects children, who experience symptoms including progressive dementia, motor decline, visual failure, challenging behaviour and epilepsy, and is life-limiting. Existing palliative treatment might reduce some symptoms, but cannot eliminate the burden of seizures and the progressively worsening effects on the whole body. There is a significant burden on society to meet medical, education and social needs, and there is a long period of complete dependence on families and carers to meet the needs of those affected with Batten disease.

Specifically, the overall objectives were:
1. Create new models, tools and technologies for developing and testing therapies
2. Further delineate disease biology and gene function to identify new therapeutic target pathways utilising yeast and pluripotent stem cell models
3. Identify biochemical therapeutic target pathways, facilitate effective evaluation of preclinical therapies and improve diagnostics
4. Extend a comprehensive natural history beyond the brain to include cardiology, the spinal cord, peripheral nervous system, psychiatric and metabolic changes
5. Identify new and repurpose existing small molecule therapy
6. Triage new compound treatments in zebrafish, a high-throughput small vertebrate model
7. Deliver and monitor new treatments using mouse models
8. Provide a novel mechanism to involve patients and their families to inform and fully contribute to therapy development and prepare for clinical trials
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.
We have created new disease models and used these to identify new compound leads. We have tested the effectiveness of gene therapy. In particular, we have successfully prevented the loss of photoreceptor cells in the CLN6 disease mouse model, and learnt which cells in the eye need to be targeted to prevent loss of sight in the CLN3 and CLN7 disease mouse models, necessary steps to developing treatment to prevent loss of sight in Batten disease. We have learnt more about disease at a cellular level as well as throughout the body in patients. We have also enabled patients, families and the wider public to engage with BATCure. These are all key steps towards understanding more about Batten disease, developing new therapies and preparing for future clinical trials.
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