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12 Headlines Emeritus Professor David Palmer has been studying Batten disease for nearly 40 years. His research team at Lincoln University is close to bringing an exciting new gene therapy for Batten disease to clinical trial. At Lincoln University we are pioneering the development of a gene therapy for Batten disease, a group of rare and devastating progressive neurodegenerative diseases in children. These are exciting times and we have reached the stage of enrolling patients for possible treatment trials, having demonstrated encouraging results in sheep. Our studies have successfully shown that brain-and-eye-directed gene therapy can slow, or halt, neurological and retinal disease in sheep with Batten disease. These promising results in large animals offer real hope for Batten disease patients. Sheep are ideal models for studying human neurological diseases. They are similarly sized, weighing 80 to 100kg as adults. Their brains are similar in physical organisation and complexity to human brains and weigh 140g at maturity - one-tenth that of adult human brains. Sheep are docile domesticated social animals that are easy to maintain, ideal for trialling therapies. The flocks we study have naturally occurring Batten disease and are now located at Lincoln University. Batten disease is caused by mutations in any one of 13 genes, including CLN5 and CLN6 forms in sheep. Over 40 years ago Professor Bob Jolly at Massey University established a flock of sheep with CLN6 Batten disease. Working with Bob and Sir John Walker and colleagues at Cambridge, we established the similarities in sheep and the major human forms of the disease. Early this century another flock of sheep with a different form of Batten disease: sheep model studies close to human trials Batten disease (CLN5) was established for therapy trials with Dr Nadia Mitchell and colleagues at Lincoln. Batten disease in sheep closely mimics the human form of the disease. Like children, affected lambs are clinically normal at birth, then deteriorate via progressive loss of vision, cognitive and motor decline and seizures resulting from progressive neuronal loss, retinal degeneration, brain inflammation and atrophy. About four New Zealand children are diagnosed with Batten disease each year. Even with intensive care, estimated to cost over $160,000 per year, few patients survive to early adulthood. Affected lambs also die prematurely, before 24 months of age, compared to their natural undisturbed lifespan of over 10 years. This allows monitoring of the safety, clinical efficacy and longer-term consequences of potential therapies in them over a timespan relevant to humans. Gene therapy is a potentially exciting treatment strategy. Viral vectors (virus particles stripped of all their genes for reproduction and virulence and instead programmed to express the functional gene) are used to deliver a functional copy of the mutant gene into the cells of patients to compensate for the defective version they have. There are two main target sites to treat the neurological and retinal disease in Batten patients - the brain and the eye. As loss of neurons ultimately causes premature death, our initial studies concentrated on brain-directed gene therapies. Our work with Associate Professors Stephanie Hughes (University of Otago) and Steven Gray (University of Texas Southwestern) delayed disease onset and progression and slowed, or halted, brain atrophy in sheep carrying the CLN5 gene. Treated sheep survived over five years of age, three times their natural life expectancy, but lost their vision. Blindness has a huge impact on the quality of life and independence of Batten disease patients. To treat the vision loss, viral vectors were delivered to the vitreous humour of one eye of affected sheep but not the other. Lincoln University post-doctoral fellow Dr Samantha Murray found that retinal structure and function were maintained in the treated eyes to 18 months of age whilst untreated eyes atrophied and lost electroretinogram signal. These animals did not receive any brain- directed treatment and still developed stereotypical neurological disease. These studies were followed up by the dual administration of CLN5 gene therapy into sheep brains and eyes. Because diagnosis of Batten disease in humans only occurs following the development of symptoms, we tested therapeutic efficacy at pre- and post- symptomatic disease stages. One of our assessment methods was to put the dual-treated sheep in a maze each month. Monthly maze testing to 24 months of age showed that treated sheep retained cognition, and vision was preserved in the majority of treated eyes. We also conducted CT and MRI studies which showed that the treatment halted stereotypical grey and white matter loss in the brain and minimised