Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Bosch, Megan E.; Aldrich, Amy; Fallet, Rachel W.; Odvody, Jessica; Burkovetskaya, Maria; Schuberth, Kaitlyn; Fitzgerald, Julie; Foust, Kevin D.; Kielian, Tammy

doi:10.1523/jneurosci.1635-16.2016

Cited by 59 publications

(56 citation statements)

References 72 publications

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“…In our hands, Cln3 Δex7/8 mice displayed significant impairments in motor function, as evident by reduced latency to fall on the accelerating rotarod (Fig 2),32 which has been attributed, in part, to excessive glutamatergic input 10, 33, 34, 35. We utilized this rotarod deficit to determine whether 3 distinct PDE4 inhibitors, including an early generation (rolipram),36 second generation (roflumilast),24 and third generation (PF‐06266047) inhibitor could improve motor function in Cln3 Δex7/8 mice over a 6‐month treatment period.…”

Section: Resultsmentioning

confidence: 54%

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

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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ObjectiveJuvenile 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 Cln3Δex7/8 mouse model of JNCL.MethodsIn a randomized, blinded study, wild‐type (WT) and Cln3Δex7/8 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 Cln3Δex7/8 animals.ResultscAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF‐06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 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.InterpretationThese studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923

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Section: Resultsmentioning

confidence: 54%

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

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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“…; Bosch et al . ). Based on our findings of exaggerated caspase activity in the TH, a key region for relaying motor signals to the cortex, we next determined if the absence of caspase 1 activity would improve motor coordination in Cln3 Δex7/8 animals.…”

Section: Resultsmentioning

confidence: 97%

“…; Bosch et al . ). Mice were not examined beyond 8 months of age because of increasing body weight that precluded accurate measurements.…”

Section: Methodsmentioning

confidence: 97%

“…All calculations were performed using custom macros developed on an AxioVision software platform (Zeiss; RRID:SCR_002677) (Bosch et al . ). Briefly, each image was divided into equal rectangles (300 × 300 μm) using an automated method, which represented regions of interest (ROI).…”

Section: Methodsmentioning

confidence: 97%

“…Band density calculations were performed using custom‐designed macros in AxioVision software (Zeiss; RRID:SCR_002677) (Bosch et al . ) and were normalized to the total protein visualized in UV irradiated gels (Gurtler et al . ; Taylor et al .…”

Section: Methodsmentioning

confidence: 99%

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Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

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Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 microglia are primed toward a pro-inflammatory phenotype typified by exaggerated caspase 1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3 mouse brain. Based on the ability of caspase 1 to cleave a large number of substrates that have been implicated in JNCL pathology, we examined the functional implications of caspase 1 inflammasome activity by crossing Cln3 and caspase 1-deficient mice to create Cln3 /Casp-1 animals. Caspase 1 deletion influenced motor behavior deficits and astrocyte activation in the context of CLN3 mutation, since both were significantly reversed in Cln3 /Casp-1 mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 mice that was partially caspase 1-dependent. However, not all CLN3 phenotypes were reversed following caspase 1 deletion, since no significant differences in lysosomal accumulation or microglial activation were observed between Cln3 and Cln3 /Casp-1 mice. Although the molecular targets of aberrant caspase 1 activity in the context of CLN3 mutation remain to be identified, our studies suggest that caspase 1 may represent a potential therapeutic target to mitigate some attributes of CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".

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Retinal Phenotype of Patients With Isolated Retinal Degeneration Due toCLN3Pathogenic Variants in a French Retinitis Pigmentosa Cohort

et al. 2021

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IMPORTANCEBiallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. OBJECTIVE To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.MAIN OUTCOME AND MEASURES Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis. RESULTSOf 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.CONCLUSIONS AND RELEVANCE These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.

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Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Cited by 59 publications

References 72 publications

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

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

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due toCLN3Pathogenic Variants in a French Retinitis Pigmentosa Cohort

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