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Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).

ABSTRACT: Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase-4 (PDE4) inhibitors (rolipram, roflumilast, and PF-06266047) could mitigate behavioral deficits and cell-specific pathology in the Cln3?ex7/8 mouse model of JNCL.In a randomized, blinded study, wild-type (WT) and Cln3?ex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal-associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3?ex7/8 animals.cAMP levels were significantly reduced in the Cln3?ex7/8 brain, and were restored by PF-06266047. PDE4 inhibitors significantly improved motor function in Cln3?ex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis.These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3?ex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909-923.

SUBMITTER: Aldrich A

PROVIDER: S-EPMC5215570 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).

Aldrich Amy A Bosch Megan E ME Fallet Rachel R Odvody Jessica J Burkovetskaya Maria M Rama Rao Kakulavarapu V KV Cooper Jonathan D JD Drack Arlene V AV Kielian Tammy T

Annals of neurology 20161123 6

<h4>Objective</h4>Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosph ...[more]

PMID: 27804148

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Project description:PurposeTo characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification.DesignRetrospective case series.ParticipantsEight children (5 female) with JNCL.MethodsReview of clinical notes, retinal imaging including fundus autofluorescence and OCT, electroretinography (ERG), and both microscopy and molecular genetic testing.Main outcome measurementsDemographic data, signs and symptoms, visual acuity (VA), fundus autofluorescence and OCT findings, ERG phenotype, and microscopy/molecular genetics.ResultsParticipants presented with rapid bilateral vision loss over 1 to 18 months, with mean VA deteriorating from 0.44 logarithm of the minimum angle of resolution (logMAR) (range, 0.20-1.78 logMAR) at baseline to 1.34 logMAR (0.30 logMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean, 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean, 8.3 years). Six children displayed eccentric fixation, and 6 children had cognitive or neurologic signs at the time of diagnosis (75%). Seven patients had bilateral bull's-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in 1 patient. OCT imaging revealed near complete loss of outer retinal layers and marked atrophy of the nerve fiber and ganglion cell layers at the central macula. An electronegative ERG was present in 4 patients (50%), but with additional a-wave reduction, there was an undetectable ERG in the remaining 4 patients. Blood film microscopy revealed vacuolated lymphocytes, and electron microscopy showed lysosomal (fingerprint) inclusions in all 8 patients.ConclusionsIn a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counseling, support, and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early-phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease.

Project description:Mutations in the CLN3 gene cause a fatal neurodegenerative disorder: juvenile CLN3 disease, also known as juvenile Batten disease. The two most commonly utilized mouse models of juvenile CLN3 disease are Cln3-knockout (Cln3(-/-)) and Cln3(Δex7/8)-knock-in mice, the latter mimicking the most frequent disease-causing human mutation. To determine which mouse model has the most pronounced neurological phenotypes that can be used as outcome measures for therapeutic studies, we compared the exploratory activity, motor function and depressive-like behavior of 1-, 3- and 6-month-old Cln3(-/-) and Cln3(Δex7/8)-knock-in mice on two different genetic backgrounds (129S6/SvEv and C57BL/6J). Although, in many cases, the behavior of Cln3(-/-) and Cln3(Δex7/8) mice was similar, we found genetic-background-, gender- and age-dependent differences between the two mouse models. We also observed large differences in the behavior of the 129S6/SvEv and C57BL/6J wild-type strains, which highlights the strong influence that genetic background can have on phenotype. Based on our results, Cln3(-/-) male mice on the 129S6/SvEv genetic background are the most appropriate candidates for therapeutic studies. They exhibit motor deficits at 1 and 6 months of age in the vertical pole test, and they were the only mice to show impaired motor coordination in the rotarod test at both 3 and 6 months. Cln3(-/-) males on the C57BL/6J background and Cln3(Δex7/8) males on the 129S6/SvEv background also provide good outcome measures for therapeutic interventions. Cln3(-/-) (C57BL/6J) males had serious difficulties in climbing down (at 1 and 6 months) and turning downward on (at 1, 3 and 6 months) the vertical pole, whereas Cln3(Δex7/8) (129S6/SvEv) males climbed down the vertical pole drastically slower than wild-type males at 3 and 6 months of age. Our study demonstrates the importance of testing mouse models on different genetic backgrounds and comparing males and females in order to find the most appropriate disease model for therapeutic studies.

Dataset Information

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).

Publications

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).

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