Therapeutic landscape for Batten disease: current treatments and future prospects

Abstract

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.

Fig. 1. Gene therapy and enzyme replacement therapy strategies in Batten disease.

a | Gene therapy as a treatment for Batten disease. Viral vectors are being explored to introduce a corrected copy of the genes mutated in Batten disease. Tropism, biodistribution and carrying capacity must be considered in selecting the type or serotype of virus to ensure the most efficient delivery. Modified adeno-associated viruses (AAVs) target expression of the CLN genes to affected cells. Once transduced into the cell, the target transgene is episomally expressed (1) (solid arrows), although limited evidence supports low-level random integration (2) (dashed arrows). The transgene is then translated, and the mature protein is trafficked to its resident location, with careful monitoring after viral transduction to ensure targeting to the correct sites. b | Enzyme replacement therapy (ERT) as a treatment for Batten disease. Multiple forms of Batten disease result from mutations in soluble lysosomal enzymes and thus might be amenable to cross-correction by ERT to partially restore levels of these enzymes in the CNS. This strategy, successfully demonstrated by cerliponase alfa, is currently available for treatment of CLN2 Batten disease. Cerliponase alfa, a recombinant proenzyme containing a mannose-6-phosphate post-translational modification, is delivered intraventricularly to the patient’s brain. This proenzyme is targeted to the mannose-6-phosphate receptor on the plasma membrane and endocytosed into the cell (1), where it fuses with the late endosome (2) before being delivered to the lysosome, where the acidic environment autocatalytically converts the enzyme to the mature, active form (3). CLN3, battenin; CLN5, ceroid lipofuscinosis neuronal protein 5; CLN6, ceroid lipofuscinosis neuronal protein 6; CLN8, ceroid lipofuscinosis neuronal protein 8; CTSD, cathepsin D; CTSF, cathepsin F; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; PPT1, palmitoyl protein thioesterase; TPP1, tripeptidyl peptidase.