Article Abstract

A canine model for neuronal ceroid lipofuscinosis highlights the promise of gene therapy for lysosomal storage diseases

Authors: Jonathan E. Phillips, Richard H. Gomer

Abstract

Patients with lysosomal storage diseases (LSDs) have abnormal lysosomal accumulation of waste products, due in most cases to enzyme deficiencies (1). The neuronal ceroid lipofuscinoses (NCLs), a subset of LSDs, are the most common childhood-onset neurodegenerative diseases and affect approximately 1 in 100,000 individuals globally (2). Children with this disease show a common set of clinical manifestations including seizures, progressive vision and motor control loss (ataxia), and accumulation of autofluorescent intracellular plaques called ceroid/lipofuscin in multiple tissues including the brain (3). The pattern of inheritance of NCLs is largely autosomal recessive, and mutations in any of 14 genes have been linked to the disease (4). Timing of disease onset correlates with which of these genes has been mutated. The two most studied and best-understood forms of NCL, Infantile NCL (INCL, onset at 6–24 months) and Late-infantile NCL (LINCL, onset at 2–4 years), are caused by mutations in the lysosomal enzymes Palmitoyl-protein thioesterase 1 (PPT1) and Tripeptidyl peptidase 1 (TPP1), respectively. There are no FDA-approved therapies for NCL, and although therapeutic treatments that manage disease symptoms are in use, the disease is inevitably fatal.

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