Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Neuronal ceroid lipofuscinosis (NCL) is a group of severe neurodegenerative disorders.
• CLN1, encoding palmitoyl protein thioesterase (PPT1), causes infantile-onset NCL.
• PPT1 deficiency impairs lysosomal degradation of S-fatty acylated proteins, leading to storage material accumulation.

Purpose of the Study:

• To evaluate the efficacy and safety of Cysteamine bitartrate (Cystagon) in juvenile-onset NCL patients with CLN1 mutations.
• To assess the impact of Cystagon on disease progression and storage material in peripheral leukocytes.

Main Methods:

• A 7-year open-label, non-randomized trial involving four individuals with juvenile CLN1-NCL treated with Cystagon.
• Gradual dose escalation of Cystagon to a target of 50 mg/kg bodyweight.
• Disease progression monitored via parental questionnaires, comparing treated individuals with five untreated controls.
• Analysis of submicroscopic lysosomal storage inclusions in mononuclear leukocytes.

Main Results:

• Cystagon treatment led to a reduction in storage material within peripheral leukocytes.
• No severe adverse events were observed; one patient experienced a dose-reducing allergic rash.
• Overall disease progression was not significantly attenuated in the treated group.
• Slower progression was noted in two individuals, but this trend was also present before treatment initiation.

Conclusions:

• Cystagon appears safe for treating juvenile CLN1-NCL, with reduced storage material as a biomarker.
• The drug did not demonstrate overall efficacy in slowing disease progression in this cohort.
• The lack of toxicity suggests potential for further investigation in infantile NCL, possibly in combination therapies.