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Intravitreal Enzyme Replacement Therapy Slows Retinopathy in Late Infantile Ceroid Lipofuscinosis Type 2
Claudia S Priglinger1, Carolina Courage2, Amelie S Lotz-Havla3
1Department of Ophthalmology, LMU University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
Insights
Intravitreal enzyme replacement therapy (IVT-ERT) with TPP1 enzyme effectively halted retinal degeneration in a patient with CLN2 disease. This treatment preserved visual function and improved quality of life, demonstrating its potential for early intervention.
Area of Science:
- Neuroscience
- Genetics
- Ophthalmology
Background:
- Ceroid lipofuscinosis type 2 (CLN2) is a rare genetic disorder caused by TPP1 gene variants, leading to progressive neurological decline and vision loss.
- Current treatments like intracerebroventricular enzyme replacement therapy (ICV-ERT) slow neurological decline but do not prevent vision loss.
- Retinal degeneration is a significant feature of CLN2 disease, often occurring after severe neurological symptoms manifest.
Purpose of the Study:
- To evaluate the clinical and ophthalmological outcomes of early intravitreal enzyme replacement therapy (IVT-ERT) in a patient with CLN2 disease and severe retinopathy.
- To assess the safety and efficacy of IVT-ERT in preserving visual function and delaying retinal degeneration.
Main Methods:
- A patient with CLN2 disease homozygous for a severe retinopathy-associated TPP1 variant received ICV-ERT and IVT-ERT in one eye.
- The treated eye received weekly IVT-ERT, while the other eye served as an untreated control.
- Ophthalmological outcomes, including best-corrected visual acuity (BCVA) and retinal structure, were monitored over 24 months.
Main Results:
- The IVT-ERT treated eye showed preserved BCVA (0.2) with spared outer retinal layers in maculopathy after 24 months.
- The untreated eye progressed to end-stage retinopathy with BCVA <0.02.
- No intraocular side effects were observed during the treatment period.
Conclusions:
- Intravitreal TPP1 enzyme replacement therapy (IVT-ERT) is a safe and effective treatment for halting retinal degeneration in CLN2 disease.
- Early IVT-ERT significantly delays retinal degeneration, preserves visual function, and enhances patient quality of life.
- This approach offers a promising therapeutic strategy for managing the ophthalmological manifestations of CLN2 disease.
Abstract:
Ceroid lipofuscinosis type 2 (CLN2) is caused by biallelic pathogenic variants in the TPP1 gene, encoding lysosomal tripeptidyl peptidase 1 (TPP1). The classical late-infantile phenotype has an age of onset between 2 and 4 years and is characterized by psychomotor regression, myoclonus, ataxia, blindness, and shortened life expectancy. Vision loss occurs due to retinal degeneration, usually when severe neurological symptoms are already evident.Intracerebroventricular enzyme replacement therapy (ICV-ERT) using recombinant human TPP1 (rhTPP-1) was shown to slow the neurological decline; however, it does not prevent loss of vision. Intravitreal rhTPP-1 (IVT-ERT) was described to halt retinal degeneration in a canine CLN2 model and a compassionate-use study in humans.We report on the clinical and ophthalmological outcome in an early-treated patient homozygous for a pathogenic variant in TPP1 known to be associated with severe CLN2 retinopathy.He was started on ICV-ERT at the age of 40 months and 4 weekly IVT-ERT in one eye at the age of 60 months. The other eye served as untreated control.Baseline best corrected visual acuity (BCVA) was 0.5 with mild bull's eye maculopathy evident in both eyes. After 24 months of IVT-ERT, BCVA in the treated eye was 0.2 with bull's eye maculopathy sparing outer retinal layers, whereas the untreated eye had progressed to endstage retinopathy and BCVA <0.02. No intraocular side effects occurred.Our results provide further evidence that IVT-ERT appears to be safe and markedly delays retinal degeneration preserving visual function and increasing the patient's quality of life, especially if started early.
