Translating preclinical models of neuronal ceroid lipofuscinosis: progress and prospects

ABSTRACT

Introduction: The Neuronal Ceroid Lipofuscinoses (NCLs, or Batten Disease) are a group of distinct inherited neurodegenerative Lysosomal Storage Disorders (LSDs) that mainly affect children and young adults. Despite recent advances, these are fatal and profoundly disabling disorders for which there remains a pressing need to devise curative therapies.

Areas covered: This article details the advances from new preclinical models of the NCLs, together with progress in developing experimental therapeutic strategies and in translating these advances into clinical trials.

Expert opinion: Animal models have been crucial for improving the understanding of the pathological mechanisms in each form, and for testing experimental therapies. With the relative success of some pre-clinical experimental approaches, several clinical trials have been initiated. These have had varying degrees of success, but the recent FDA approval of recombinant enzyme replacement for CLN2 disease, an approach initially tested in mouse and dog models, is a positive step towards the goal of effective therapies for the NCLs. As new data emerges from preclinical models about NCL pathogenesis, it is increasingly likely that a combination of therapies that either target different regions of the body, or multiple disease mechanisms, will be required to effectively treat the NCLs.

KEYWORDS:

• Batten disease
• neuronal ceroid lipofuscinosis
• enzyme replacement
• gene therapy
• neural stem cell transplantation
• small molecule therapies
• combination treatments
• preclinical testing
• clinical trials

Article highlights

• The Neuronal Ceroid Lipofuscinoses (NCLs) are a group of fatal neurodegenerative lysosomal storage disorders.

• There have been significant advances in generating and characterizing small and large vertebrate animal models of the NCLs that accurately recapitulate the human diseases.

• The recent FDA approval of a recombinant enzyme replacement for CLN2 disease, is a landmark moment, as it is the first commercially available drug for any form of NCL.

• However, more work is required for make therapies for other forms of NCL readily available, with promising pre-clinical data for targeted gene therapy approaches now emerging.

• Recent evidence of significant pathology outside the brain and nervous system in these diseases emphasizes the need for a whole body therapeutic approach to ensure effective therapies.

This box summarizes key points contained in the article.

Declaration of interest

J Cooper is a consultant for BioMarin Pharmaceuticals Inc and Regenexbio. He has received research funding from BioMarin Pharmaceuticals Inc., which included the pre-clinical pathology studies in a dog model of CLN2 disease. These lead to the successful clinical trial of enzyme replacement in this form of NCL, and its subsequent approval by the FDA, but J Cooper was not involved in these clinical studies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded