Roslin Institute studies with sheep show potential benefit of enzyme replacement therapy for incurable neurological diseases. Studies of a rare nervous system disorder that causes dementia and early death in children have revealed a possible treatment for the condition. Regular infusions of a key enzyme missing in children with infantile Batten disease, also called CLN1 disease, led to improvements in mice and sheep with a similar genetic disorder. The results of a study led by Washington University School of Medicine in St. Louis and the Roslin Institute could help develop effective treatments for children with the disease, which can lead to vision loss, cognitive and movement disorders, seizures and early death. Development of enzyme replacement therapy Scientists studied the effect of administering doses of the enzyme known as PPT1 in mice and sheep with the same defective gene that causes the disease in children. Monthly administration of the PPT1 enzyme to the brains of mice resulted in improved motor function, reduced signs of disease in brain cells and reduced loss of brain matter during the six-month treatment. The research team first reviewed the enzyme dose and route of administration required for a beneficial effect in mice and extrapolated its findings to determine effective enzyme infusion treatments for affected sheep. This critical step demonstrated that treatments that show promise in mice can be translated to have a similar positive treatment effect in a much larger brain. Their study built on a similar approach for another form of Batten disease, known as CLN2, which has led to a therapy called cerliponase alfa, or Brineura. This was approved by the NHS following successful clinical trials as part of a collaboration between centres around the world. The recent study in mice and sheep provided insights into how the therapy works by testing the basic principles in mice and then refining them in a mammal whose brain size and complexity is comparable to that of children. The research team hopes to conduct further studies to refine the timing and dosage of enzyme replacement therapy to develop an effective treatment for this devastating childhood disease. Image Genome editing technology used Batten disease, one of several conditions known as lysosomal storage disorders, is an umbrella term for a group of neurodegenerative conditions caused by genetic mutations that impair the cells' waste disposal and recycling system. These conditions can occur at different stages of childhood, depending on which gene is deficient. The PPT1-deficient CLN1 form of the disease develops in early childhood, progresses rapidly, and there is currently no therapy. The Roslin team has developed a sheep model for this disorder using CRISPR/Cas9 genome editing technology so that therapeutic trials like this can be conducted. This has allowed researchers to better understand the mechanisms underlying disease progression and evaluate new methods for treating the condition. The animals show many features of the disease in children, from signs of disease in the cells to changes in the size of the brain. The study was published in the Journal of Clinical Investigation. This study could only have been done by a collaborative research team. Such work is a key step towards everyone’s ultimate goal of safely carrying out clinical tests of potential treatments in children affected by this devastating condition. Through studies in sheep, we gain invaluable insights into the progression of this condition which can guide our work towards developing an effective therapy. Professor Tom Wishart Professor of Molecular Anatomy, the Roslin Institute Our work together with colleagues at the Roslin Institute has shown the potential for this new therapy to treat this devastating fatal disease. Not only did we improve disease in mice, but we were successful in scaling it to have similar partial efficacy in the much larger brain of a sheep model of the same disease. This is the result of combining our expertise, using models that were made specially to test therapies like this. Our goal is to be able to treat children with this disease, and this is an important step towards achieving this. Professor Jonathan D Cooper Professor of Pediatrics, Genetics and Neurology, Washington University School of Medicine in St. Louis Related Links The Roslin Institute "Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep" publication Tom Wishart profile This article was published on 2022-11-03
