An update on the progress of preclinical models for guiding therapeutic management of neuronal ceroid lipofuscinosis

ABSTRACT

Introduction: The neuronal ceroid lipofuscinoses (NCLs) are a group of pediatric inherited neurodegenerative disorders affecting children and young adults. All forms of NCL are fatal and with no curative therapies available there is a pressing need to model their pathology in biological model systems to enable the systematic and rigorous testing of preclinical therapies.

Areas covered: This article discusses and provides an update on the recent advances in modelling NCL disease pathology in various different model systems and their relevance to testing preclinical therapies so as to ensure optimal translation into human patients. The research articles discussed here were curated from PubMed (Last accessed-12.4.19) and Google Scholar (Last access-12.4.19) databases.

Expert opinion: Both in vitro and in vivo biological model systems have been established for various forms of NCL. These have informed us about pathophysiology, revealed novel therapeutic targets, and provided landmarks of disease progression against which to test potential therapies. Studying NCL pathology across different species has been very informative regarding where therapies need to be delivered with an increasing focus on disease outside the brain. Testing such therapies in animal models of increasing complexity has allowed the translation of more efficacious therapies for clinical trials.

KEYWORDS:

• Neuronal ceroid lipofuscinoses
• Batten disease
• lysosomal storage disorders
• CRISPR/Cas9
• large animal models
• enzyme replacement therapy
• gene therapy

Article highlights

• The neuronal ceroid lipofuscinoses are a group of fatal, inherited neurodegenerative pediatric lysosomal disorders.

• Currently, treatments for most forms of NCL are palliative and symptomatic only; with the FDA-approved drug, Brineura (Cerliponase alpha) for CLN2 disease the only disease-limiting therapy available for any form.

• Modeling disease pathology in biological systems is particularly relevant given the rarity of these diseases and the need to effectively and systematically test therapies preclinically.

• While there are a multitude of naturally occurring and generated biological models of NCL disease, recent technological advances in genome editing have allowed for more accurate genetic models of the NCLs, particularly larger animal models.

• More accurate models of NCL are likely to inform therapies that target different pathological processes, and affected anatomical regions and may necessitate combinatorial therapies.

• The increased use of models from multiple species to test therapies has proved to be particularly successful for some forms of NCL and highlights the need for similar models across other forms of NCL.

This box summarizes the key points contained in the article.

Declaration of interest

JD Cooper has been a consultant for, or in receipt of research support from, BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Regenexbio Inc., CereSpir Inc, and JCR Pharmaceuticals Co, Ltd. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

There is no funding related to this review article.