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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BATCure (Developing new therapies for Batten disease)

Teaser

Neuronal ceroid lipofuscinoses (NCL), commonly known as Batten disease, is the most common of the rare neurodegenerative disorders of children, affecting approximately 14,000 world-wide, with around 1,400 new cases each year. It is a devastating and severely debilitating group...

Summary

Neuronal ceroid lipofuscinoses (NCL), commonly known as Batten disease, is the most common of the rare neurodegenerative disorders of children, affecting approximately 14,000 world-wide, with around 1,400 new cases each year. It is a devastating and severely debilitating group of genetic diseases. There are no established curative treatments yet 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 will focus 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, for which no therapy is currently within sight. 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.

This project will focus on developing treatments for three distinct diseases that account for more than half of all diagnosed cases of Batten disease, directly affecting the lives of thousands of living children and young adults, for which no therapy is currently available.
By the end of the project, BATCure expects to have at least one lead therapy ready for phase 1/2 clinical trial.
Specifically, the overall objectives are:
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

Work performed

A summary of the progress made in the first 18 months of BATCure is presented by work package.

WP1 New models: We have made use of existing and generated new models of CLN3, CLN6 and CLN7 disease to examine disease mechanisms, treatments and diagnosis. These include new yeast strains to model different mutations of CLN3 disease and pluripotent cell models derived from human patient cells. We have brought together the latest mouse models for CLN3, CLN6 and CLN7 diseases. New zebrafish models are being made for all types. We are also still making other new tools such as antibodies to help assess the role of proteins, their distribution and aid in diagnosis.

WP2 Pathway leads: Genes and pathways have been identified in yeast that affect the growth of yeast strains modelling CLN3 disease. We have successfully purified and extended functional analysis of the CLN3 protein in its role in lysosomal Ca2+ homeostasis. Gene-regulatory networks have been constructed for CLN3, CLN6 and CLN7. Metabolic reprogramming has been confirmed in CLN3, CLN6 and CLN7 disease, and the heat shock response, UPR and ER stress has been analysed in CLN3 and CLN7 diseases.

WP3 Metabolome: A difference was observed between the metabolic profiles of a yeast model of CLN3 disease, with treatment using compounds changing the levels of key metabolites. Tissues showing the most pronounced differences in metabolic profile in a mouse CLN3 disease model were identified.

WP4 Natural history: A set of clinical testing tools to better understand whether organs beyond the brain are potential targets for experimental therapies has been established. A study of brain volumetric data in CLN3 patients is almost complete. New information has been collected about spinal pathology, and how it differs between different forms of NCL. Similar work is ongoing in the mouse disease models.

WP5 Compound leads: A drug discovery effort that included screening FDA-approved libraries has identified compound hits. Structure Activity Relationship modelling of the first lead compound is well underway.

WP6 Zebrafish triage: Study of the first mutant fish is underway.

WP7 Gene therapy: Mouse models for CLN3, CLN6 and CLN7 diseases have been characterised to define suitable endpoints to show treatment benefit. Ocular and CNS gene therapy experiments have started for all three genes. For CLN6 disease, it has been possible to prevent the loss of photoreceptors and preserve retinal function for more than 9 months.

WP8 Drug therapy: Studies of neurotransmitter levels have been initiated in the CLN7 disease mouse, to link with behaviour and pathological changes.

WP9 Patient organisation involvement: A range of events, resources and communication channels have been established to promote BATCure and enable the participation of patients, families, researchers, professionals and the wider public in the project. A key activity has been the design and implementation of an online family survey, giving patients and affected families across the EU a voice within the research.

Final results

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, a necessary step to developing treatment to prevent loss of sight in Batten disease. We have learnt more about disease at a cellular level as well as in patients. We have also enabled patients, families and the wider public to engage with BATCure. These are all key steps towards developing new therapies and preparing for future clinical trials.

Website & more info

More info: http://www.batcure.eu.