Australia and New Zealand
Batten Disease Research Grant Program

CLN3 disease affects the brain of children, causing dementia and premature death. Whilst we know that >70 pathological variants in the CLN3 gene cause disease, we know surprisingly little about the processes that occur cells in the eye and brain to become dysfunctional and die. Furthermore, most of what we do know is derived from studying mouse models of CLN3 disease that model the commonly occurring 1 kb deletion CLN3 variant. Thus, for many people with CLN3 disease, there is little, or even no data relevant to the CLN3 variants causing their disease.

This project seeks to overcome this lack of data, through generating a powerful and unique resource with which to study CLN3 disease. We will use advanced techniques in stem cell biology and gene editing technology to produce a collection of stem cell lines that will enable us to begin determining how CLN3 gene variants that have different effects on the CLN3 protein, or which are associated with “Classic” or “Protracted” clinical descriptions of the disease.

This stem cell collection represents the first step in larger subsequent studies focused on understanding how different CLN3 gene variants change the function of cells in the eye and the brain. Through sharing the stem cell collection widely with other researchers, this project will provide a means to better understand the disease and in turn, identify and test new treatment strategies.

BDSRA Australia wishes to thank the Beyond Batten Disease Foundation for partnering with us to co-fund 50% of this grant.

Gene therapies developed in naturally occurring sheep models of CLN5 and CLN6 Batten disease at Lincoln University (NZ) look encouraging. In particular, the single delivery of our CLN5 gene therapy product to the fluid-filled spaces (lateral ventricles) in the brain of affected sheep protected against neurological disease and brain shrinkage. In addition, delivery into the jelly-like fluid of the eye (vitreous humour) protected against vision loss. Based on these studies, our CLN5 gene therapy was recently approved for use in children with CLN5 Batten disease (Clinicaltrials.gov identifier: NCT05228145).

As we potentially begin to treat the neurological disease and loss of vision in Batten disease, we need to consider the impact of the disease on the other peripheral organs. The disease-causing mutation is present in all cells of the body and the Batten disease proteins are expressed across the periphery, including the heart, lungs, liver, pancreas, kidneys, gastrointestinal tract, muscle, endocrine tissues, and reproductive organs. With the prospect of treated children living longer without neurological disease, we need to pre-empt what may come next and be prepared to treat, or ideally prevent, disease in the periphery.

This study will examine disease pathology in peripheral tissues, such as those listed above, from healthy, affected and treated sheep of different ages. Overall, we aim to understand how peripheral pathology manifests, if at all, within the normal lifespan of affected sheep, but also determine if peripheral pathologies may be unmasked in our treated sheep with much longer than expected life spans. Concurrently we will examine haematology, biochemistry, and inflammatory markers in blood from healthy, affected and treated sheep to look for any potential biomarkers, which is severely lacking in human NCL medicine.

This research proposes to phenotype speech and language in Batten Disease (CLN2 and CLN3 subtypes) for the first time. In all forms of neuronal ceroid lipofuscinoses (NCLs), or Batten Disease, symptoms may include a decline in motor skills, cognition and vision, epilepsy, sleep difficulties, psychiatric symptoms and deteriorating speech and language. Phenotyping these symptoms is valuable to measure disease progression and the efficacy of precision medicine trials. Clinical trials are being conducted to investigate the efficacy of treatments, including enzyme replacement, stem cell and adeno-associated virus-mediated gene therapies.

Although progressive speech and language impairment is implicated in all forms of Batten Disease, there has been no systematic characterisation of speech and language. Phenotyping informs the implementation of clinical trials. Speech and language characterisation provides a window into the neurobiology of Batten Disease. It will help inform families and clinicians’ decision making as a child’s speech progresses from using speech to using Augmentative and Alternative Communication to communicate.

This research has three specific aims:

• i.   Provide evidence-based speech and language information in Batten Disease to guide management for families and clinicians
• ii.  Novel phenotyping data will enable more targeted speech therapies to meet patients’ needs
• iii. Provide information on the best speech and language measures that can be used to measure effectiveness of future clinical trials.

We will use assessment tools that will, for the first time, facilitate inclusion of children with all types of Batten disease enabling broader generalisability of findings and uptake of these measures in trials. This will also allow comparison of sub-types of Batten disease.

*Note, if you are a parent or guardian of a child with Batten disease (in Australia or New Zealand) and would like to know more about being involved in this study, please contact BDSRA Australia at research@bdsraaustralia.org.