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.

The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

In Saccharomyces cerevisiae, transport of arginine into the vacuole has previously been shown to be facilitated by a putative H ؉ ͞ arginine antiport. We confirm that transport of arginine into isolated yeast vacuoles requires ATP and we demonstrate a requirement for a functional vacuolar H ؉ -ATPase. We previously reported that deletion of BTN1 (btn1-⌬), an ortholog of the human Batten disease gene CLN3, resulted in a decrease in vacuolar pH during early growth. We report that this altered vacuolar pH in btn1-⌬ strains underlies a lack of arginine transport into the vacuole, which results in a depletion of endogenous vacuolar arginine levels. This arginine transport defect in btn1-⌬ is complemented by expression of either BTN1 or the human CLN3 gene and strongly suggests a function for transport of, or regulation of the transport of, basic amino acids into the vacuole or lysosome for yeast Btn1p, and human CLN3 protein, respectively. We propose that defective transport at the lysosomal membrane caused by an absence of functional CLN3 is the primary biochemical defect that results in Batten disease.

Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are responsible for the neurodegenerative disorder juvenile Batten disease. A previous study on the yeast homolog to CLN3, designated Btn1p, revealed a potential role for CLN3 in the transport of arginine into the yeast vacuole, the equivalent organelle to the mammalian lysosome. Lysosomes isolated from lymphoblast cell lines, established from individuals with juvenile Batten disease-bearing mutations in CLN3, but not age-matched controls, demonstrate defective transport of arginine. Furthermore, we show that there is a depletion of arginine in cells derived from individuals with juvenile Batten disease. We have, therefore, characterized lysosomal arginine transport in normal lysosomes and show that it is ATP-, v-ATPase- and cationic-dependent. This and previous studies have shown that both arginine and lysine are transported by the same transport system, designated system c. However, we report that lysosomes isolated from juvenile Batten disease lymphoblasts are only defective for arginine transport. These results suggest that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell. This assertion is supported by two other experimental approaches. First, an antibody to CLN3 can block lysosomal arginine transport and second, expression of CLN3 in JNCL cells using a lentiviral vector can restore lysosomal arginine transport. CLN3 may have a role in regulating intracellular levels of arginine possibly through control of the transport of this amino acid into lysosomes.