Advances in the treatment of neuronal ceroid lipofuscinosis

ABSTRACT

Introduction: Neuronal ceroid lipofuscinoses (NCL) are neurodegenerative lysosomal storage disorders typically characterized by cognitive and visual impairments, epileptic seizures, ataxia, and deterioration of motor skills. Recent success of Brineura® for the treatment of neurologic manifestations of CLN2 disease has led to renewed interest in therapeutics for NCL. Despite complex challenges associated with CNS therapy, treatment modalities such as enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy have been evaluated. Owing to the complexity of clinical endpoints which are often reliant on subjective clinical scales for the evaluation of candidate therapies, development of quantitative biomarkers for NCLs has become a necessity for the validation of potential treatments.

Areas covered: For each NCL subtype, this review covers natural histories, animal models, biomarkers, therapeutic approaches, and preclinical and clinical research for therapeutic development. It corresponds to literature covering the years 1968-2019, with emphasis on the last decade.

Expert opinion: Much progress has been made in NCL research, including better animal models, biomarkers and improved therapeutics with many of them reaching the clinical trial stage. In the future, successful therapies may involve the combination of two or more therapeutic modalities to provide therapeutic benefit especially as the patients grow older.

KEYWORDS:

• Neuronal ceroid lipofuscinoses (NCL)
• ceroid lipofuscinosis
• neuronal (CLN)
• palmitoyl protein thioesterase-1 (PPT1)
• tripeptidyl peptidase-1 (TPP1)
• enzyme replacement therapy (ERT)
• gene therapy
• adeno-associated virus (AAV)
• clinical trials

Article highlights

• Neuronal ceroid lipofuscinoses (NCL) are a collection of neurologic disorders involving defective lysosomal processing enzymes or receptors that lead to cognitive and visual impairments, seizures, deterioration of motor/language skills, and premature death.

• Many experimental animal models (mice, dogs, pigs, and sheep) for the NCLs have been created or identified, which possess genomic mutations responsible for NCL subtypes, allowing investigations of safety and efficacy of new therapeutics in preclinical studies.

• Development of quantitative biomarkers in the blood or CSF for NCLs, enabling investigators to track biochemically the improvement or decline of disease-related phenotypes, is an important component in the validation of potential treatments.

• Review of the challenges of delivery of treatments, primarily due to CNS involvement and the blood-brain barrier, and possible therapeutic approaches for the development of treatment modalities for NCL, such as enzyme replacement therapy, cell therapy, gene therapy, and pharmacological drugs.

• Current therapies for each of the NCL subtypes are discussed with emphasis on the most promising ones being translated to clinical trials, such as clinical development of ERT for CLN2 (Brineura®), immunosuppression for CLN3 (CellCept®), and gene therapy vectors for CLN1, CLN2, CLN3 and CLN6.

• Gene therapy clinical trials using adeno-associated virus (AAV) to deliver the normal NCL-relevant gene to the CNS are underway and are being evaluated for safety and efficacy.

• A combination approach using multiple treatment modalities may be the key to developing the most promising therapeutic approaches for NCLs.

Declaration of interest

R Crystal is a consultant to BioMarin. 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.

Reviewer disclosures

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

Additional information

Funding

This paper was funded by NIH 1R01NS061848, U01NS047458, and Foundation for Life, Chicago, IL.