Therapeutic landscape for Batten disease: current treatments and future prospects

Abstract

Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten disease. Here, we provide an overview of the promising therapeutic avenues for Batten disease, highlighting current FDA-approved clinical trials and prospective future treatments.

Key points

  • The FDA approval of the enzyme replacement therapy cerliponase alfa (Brineura) for the treatment of CLN2 Batten disease is an important milestone in Batten disease therapy.

  • Promising results from preclinical research indicate that gene therapy — particularly approaches that use adeno-associated virus — represents a promising treatment option for patients in the near future.

  • Many of the preclinical strategies being explored for the treatment of one form of Batten disease could have applications across multiple subtypes of Batten disease and even other lysosomal storage disorders.

  • Investigators now recognize that a single treatment might not be sufficient to halt disease progression and are exploring combinatorial approaches to tackle multiple aspects of Batten disease progression.

  • A battery of new preclinical and clinical tools have been developed that facilitate effective therapy development in Batten disease, enabling an unprecedented acceleration in drug discovery for these fatal disorders.

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Fig. 1: Gene therapy and enzyme replacement therapy strategies in Batten disease.

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Acknowledgements

T.B.J., J.T.C., K.A.W. and J.M.W. are supported in part by funding to J.M.W. from the Charlotte and Gwenyth Gray Foundation, the Haley’s Heroes Foundation, the Beat Batten Foundation and the Sebastian Velona Foundation and from NIH R01NS082283.

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Nature Reviews Neurology thanks J. Mink and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Batten disease mutation database: http://www.ucl.ac.uk/ncl

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Johnson, T.B., Cain, J.T., White, K.A. et al. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 15, 161–178 (2019). https://doi.org/10.1038/s41582-019-0138-8

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