Intravitreal enzyme replacement preserves retinal structure and function in canine CLN2 neuronal ceroid lipofuscinosis

Whiting, Rebecca E.H.; Pearce, Jacqueline W.; Vansteenkiste, Daniella P.; Bibi, Katherine; Lim, Stefanie; Kick, Grace Robinson; Castaner, Leilani J.; Sinclair, John; Chandra, Sundeep; Nguyen, Annalisa; O’Neill, Charles; Katz, Martin L.

doi:10.1016/j.exer.2020.108130

Cited by 15 publications

(6 citation statements)

References 45 publications

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“…There have been encouraging reports of treatments in CLN2 slowing decline [16][17][18]. ERT administration does not alter the progressive retinal degeneration [18], probably because of the spectrum of the eye's immune privilege and blood-retina CNS barrier [19], but intravitreal administration of rhTPP1 has slowed retinal degeneration in four TPP1-null dogs [20]. The advent of treatments for CLN2 disease highlights an urgent need to better characterise the natural history of CLN2 retinopathy, which is shielded from some treatments by the blood-retina barrier.…”

Section: Introductionmentioning

confidence: 99%

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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Background Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. Subjects and methods We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. Results ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. Conclusion ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.

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Section: Introductionmentioning

confidence: 99%

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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“…We hypothesise that the reason ICV ERT is not an effective treatment for CLN2 retinal dystrophy is because it does not cross the blood brain barrier and therefore does not have access to the vitreous or retina. Consistent with this hypothesis is recent evidence that regular intravitreal injections of ERT (IVT ERT) in combination with ICV ERT, but not ICV ERT alone, can rescue retinal dystrophy in a canine model of the disease [5]. We therefore designed a first-in-man study of the feasibility and safety of IVT ERT in human CLN2 patients to test the hypothesis that IVT ERT could slow down the progression of retinal dystrophy in CLN2 patients also receiving ICV ERT.…”

Section: Introductionmentioning

confidence: 86%

“…IVT ERT was prepared using overage from brineura sourced for ICV ERT in the same patients (method described in supplementary material). This dose was chosen by proportionally scaling up from the 0.1 mg rhTPP-1 used previously in a canine study [5], assuming the human vitreous volume to be approximately double that of the dog. Following each injection, the patency of the central retinal artery was checked and an anterior chamber paracentesis was performed if occluded.…”

Section: Protocolmentioning

confidence: 99%

First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy

Wawrzynski,

Martinez,

Thompson

et al. 2023

Eye

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Background/Objectives CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. Subjects/methods 8 children aged 5–9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12–18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. Results No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). Conclusions Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

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“…To address retinal degeneration, Whiting et al [26 ▪▪ ] conducted a preclinical study in a CLN2 canine model to determine if intravitreal injections of recombinant human TTP1 (0.1–0.3 mg of rhTPP1) could slow or stop the decline in retinal function and degeneration when administered after the onset of retinal impairment. Dogs with TPP1 deficiency were given intravitreal rhTPP1 injections in one eye and a vehicle in the other eye.…”

Section: Intravitreal Injections In Canine Modelsmentioning

confidence: 99%

Intravitreal enzyme replacement for inherited retinal diseases

Rodriguez-Martinez,

Wawrzynski,

Henderson

2023

Current Opinion in Ophthalmology

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Purpose of review This paper provides an update on intravitreal (IVT) enzyme replacement therapy (ERT) in metabolic retinal diseases; particularly neuronal ceroid lipofuscinosis type 2 (CLN2) also known as Batten disease. Recent findings ERT is being explored in CLN2 related Batten disease, a fatal neurodegenerative condition associated with retinopathy and blindness that is caused by the deficiency of lysosomal enzyme TPP1. Cerliponase alfa, a recombinant human tripeptidyl-peptidase1 (rhTPP1) administered by intraventricular infusions has been demonstrated to slow the rate of neurodegenerative decline but not retinopathy. A preclinical study of IVT rhTPP1 in a CLN2 canine model demonstrated efficacy in preserving retinal function and retinal morphology shown on histology. More recently, intravitreal (IVT) administration of rhTPP1 was reported in a first-in-human compassionate use study. Patients received 12–18 months of 8-weekly IVT ERT (0.2 mg rhTPP-1 in 0.05 ml) in one eye. No significant ocular adverse reactions were reported. Treatment decreased the rate of retinal thinning but modestly. Summary The evidence suggests that IVT ERT with rhTPP1 may be a safe and effective treatment for CLN2 retinopathy. However, the optimal dosage and frequency to achieve the best possible outcomes requires further investigation as does patient selection.

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Intravitreal enzyme replacement preserves retinal structure and function in canine CLN2 neuronal ceroid lipofuscinosis

Cited by 15 publications

References 45 publications

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy

Intravitreal enzyme replacement for inherited retinal diseases

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