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1.
Clin Transl Sci ; 17(6): e13858, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38932491

RESUMO

Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor-predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1+/ex42del miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from NF1+/ex42del and wild-type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance-preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.


Assuntos
Modelos Animais de Doenças , Neurofibromatose 1 , Animais , Neurofibromatose 1/fisiopatologia , Neurofibromatose 1/complicações , Neurofibromatose 1/metabolismo , Camundongos , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Comportamento Animal , Masculino , Hipocampo/patologia , Hipocampo/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Humanos , Astrócitos/metabolismo , Astrócitos/patologia , Feminino
2.
bioRxiv ; 2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37790379

RESUMO

Lysosomal storage disorders (LSDs) are a genetically and clinically diverse group of diseases characterized by lysosomal dysfunction. Batten disease is a family of severe LSDs primarily impacting the central nervous system. Here we show that AF38469, a small molecule inhibitor of sortilin, improves lysosomal and glial pathology across multiple LSD models. Live-cell imaging and comparative transcriptomics demonstrates that the transcription factor EB (TFEB), an upstream regulator of lysosomal biogenesis, is activated upon treatment with AF38469. Utilizing CLN2 and CLN3 Batten disease mouse models, we performed a short-term efficacy study and show that treatment with AF38469 prevents the accumulation of lysosomal storage material and the development of neuroinflammation, key disease associated pathologies. Tremor phenotypes, an early behavioral phenotype in the CLN2 disease model, were also completely rescued. These findings reveal sortilin inhibition as a novel and highly efficacious therapeutic modality for the treatment of multiple forms of Batten disease.

3.
Dis Model Mech ; 16(8)2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37305926

RESUMO

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span and inconsistent subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, thereby limiting their use in preclinical studies. Here, we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with retinal degeneration and motor abnormalities, similar to deficits seen in humans diagnosed with the disease. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology, and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease-modifying therapeutics.


Assuntos
Doenças por Armazenamento dos Lisossomos , Lipofuscinoses Ceroides Neuronais , Camundongos , Humanos , Animais , Suínos , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/patologia , Chaperonas Moleculares , Retina/patologia , Fenótipo , Modelos Animais de Doenças , Glicoproteínas de Membrana/genética
4.
Front Genet ; 14: 1118649, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37035740

RESUMO

CLN3 disease, caused by biallelic mutations in the CLN3 gene, is a rare pediatric neurodegenerative disease that has no cure or disease modifying treatment. The development of effective treatments has been hindered by a lack of etiological knowledge, but gene replacement has emerged as a promising therapeutic platform for such disorders. Here, we utilize a mouse model of CLN3 disease to test the safety and efficacy of a cerebrospinal fluid-delivered AAV9 gene therapy with a study design optimized for translatability. In this model, postnatal day one administration of the gene therapy virus resulted in robust expression of human CLN3 throughout the CNS over the 24-month duration of the study. A range of histopathological and behavioral parameters were assayed, with the therapy consistently and persistently rescuing a number of hallmarks of disease while being safe and well-tolerated. Together, the results show great promise for translation of the therapy into the clinic, prompting the launch of a first-in-human clinical trial (NCT03770572).

5.
Sci Rep ; 13(1): 5146, 2023 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-36991106

RESUMO

Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease (Batten disease) is a rare pediatric disease, with symptom development leading to clinical diagnosis. Early diagnosis and effective tracking of disease progression are required for treatment. We hypothesize that brain volumetry is valuable in identifying CLN2 disease at an early stage and tracking disease progression in a genetically modified miniswine model. CLN2R208X/R208X miniswine and wild type controls were evaluated at 12- and 17-months of age, correlating to early and late stages of disease progression. Magnetic resonance imaging (MRI) T1- and T2-weighted data were acquired. Total intercranial, gray matter, cerebrospinal fluid, white matter, caudate, putamen, and ventricle volumes were calculated and expressed as proportions of the intracranial volume. The brain regions were compared between timepoints and cohorts using Gardner-Altman plots, mean differences, and confidence intervals. At an early stage of disease, the total intracranial volume (- 9.06 cm3), gray matter (- 4.37% 95 CI - 7.41; - 1.83), caudate (- 0.16%, 95 CI - 0.24; - 0.08) and putamen (- 0.11% 95 CI - 0.23; - 0.02) were all notably smaller in CLN2R208X/R208X miniswines versus WT, while cerebrospinal fluid was larger (+ 3.42%, 95 CI 2.54; 6.18). As the disease progressed to a later stage, the difference between the gray matter (- 8.27%, 95 CI - 10.1; - 5.56) and cerebrospinal fluid (+ 6.88%, 95 CI 4.31; 8.51) continued to become more pronounced, while others remained stable. MRI brain volumetry in this miniswine model of CLN2 disease is sensitive to early disease detection and longitudinal change monitoring, providing a valuable tool for pre-clinical treatment development and evaluation.


Assuntos
Lipofuscinoses Ceroides Neuronais , Tripeptidil-Peptidase 1 , Criança , Humanos , Aminopeptidases , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Dipeptidil Peptidases e Tripeptidil Peptidases , Progressão da Doença , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Lipofuscinoses Ceroides Neuronais/patologia , Serina Proteases , Suínos , Animais
6.
Orphanet J Rare Dis ; 17(1): 411, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369162

RESUMO

BACKGROUND: CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. RESULTS: Several notable sex differences were observed in the presentation of brain pathology, including Cln8mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. CONCLUSIONS: Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact.


Assuntos
Lipofuscinoses Ceroides Neuronais , Camundongos , Animais , Feminino , Masculino , Lipofuscinoses Ceroides Neuronais/genética , Proteínas de Membrana/genética , Modelos Animais de Doenças , Efeitos Psicossociais da Doença , Glicoproteínas de Membrana , Chaperonas Moleculares
7.
Neurotherapeutics ; 19(6): 1905-1919, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36100791

RESUMO

CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2R208X/R208X porcine model of CLN2 disease. We present comprehensive characterization showing behavioral, pathological, and visual phenotypes that recapitulate those seen in CLN2 patients. CLN2R208X/R208X miniswine present with gait abnormalities at 6 months of age, ERG waveform declines at 6-9 months, vision loss at 11 months, cognitive declines at 12 months, seizures by 15 months, and early death at 18 months due to failure to thrive. CLN2R208X/R208X miniswine also showed classic storage material accumulation and glial activation in the brain at 6 months, and cortical atrophy at 12 months. Thus, the CLN2R208X/R208X miniswine model is a valuable resource for biomarker discovery and therapeutic development in CLN2 disease.


Assuntos
Lipofuscinoses Ceroides Neuronais , Camundongos , Animais , Suínos , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/patologia , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Aminopeptidases/genética , Aminopeptidases/uso terapêutico , Serina Proteases/genética , Serina Proteases/uso terapêutico , Fenótipo , Convulsões/tratamento farmacológico
8.
Mol Ther Methods Clin Dev ; 20: 497-507, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33665223

RESUMO

Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6 nclf ), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6 nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6 nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6 nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration.

9.
Am J Prev Med ; 60(5): 639-647, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33602533

RESUMO

INTRODUCTION: In December 2019, the U.S. raised the minimum legal sales age of tobacco to 21 years, a law commonly known as Tobacco 21. This study examines local Tobacco 21 policies for the inclusion of model policy components: comprehensive tobacco definition, age verification and tobacco access, enforcement measures, tobacco retail license, and violation penalties. METHODS: A document analysis of Tobacco 21 local policies passed in the U.S. before July 1, 2019 (N=477) was conducted in May 2020 using a Tobacco 21 policy assessment tool. Policies were coded by 2 independent coders for the inclusion of components. RESULTS: Many localities included model component: comprehensive tobacco definition (65%), appearance age (70.9%), local tobacco retail license (72%), a graduated monetary penalty structure (93%), and tobacco retail license suspensions or revocations (74%) for repeated violations. However, only 17.4% of policies included an appearance age in compliance with federal law (30 years). Furthermore, few policies included enforcement components, such as a mandatory number of inspections (5.9%) or compliance checks (6.7%) per year, or a minimum age for the underage purchasers used during compliance checks (8.4%). CONCLUSIONS: Local policies can play an important role in tobacco control by providing an added layer to ensure adequate enforcement of age-restriction policies and allow an avenue to introduce strict measures that may diffuse into higher branches of government for policy adoption. Although many local Tobacco 21 policies fill regulatory gaps within the state and federal laws, often there is a lack of model components to ensure that policies are implemented as intended.


Assuntos
Nicotiana , Produtos do Tabaco , Adulto , Comércio , Humanos , Política Pública , Uso de Tabaco
10.
Mol Ther ; 29(1): 162-175, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33010819

RESUMO

CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (i.c.v.) delivered self-complementary adeno-associated virus serotype 9 (scAAV9) gene therapy vector driving expression of human CLN8. A single neonatal injection was safe and well tolerated, resulting in robust transgene expression throughout the CNS from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. While it is unclear whether some of these behavioral improvements relate to preserved visual function, improvements in learning/memory, or other central or peripheral benefits, these results demonstrate, by far, the most successful degree of rescue reported in an animal model of CLN8 disease, and they support further development of gene therapy for this disorder.


Assuntos
Dependovirus/genética , Terapia Genética , Vetores Genéticos/genética , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/terapia , Animais , Comportamento Animal , Modelos Animais de Doenças , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Transgenes , Resultado do Tratamento
11.
Prog Neurobiol ; 189: 101789, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32198061

RESUMO

While research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single "needle in a haystack", we embrace the idea that disease progression, in mice and patients alike, is a diverse phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future.


Assuntos
Biomarcadores , Encéfalo/diagnóstico por imagem , Progressão da Doença , Transtornos Neurológicos da Marcha/diagnóstico , Lipofuscinoses Ceroides Neuronais/diagnóstico , Animais , Fenômenos Biomecânicos , Encéfalo/metabolismo , Encéfalo/patologia , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/patologia , Transtornos Neurológicos da Marcha/fisiopatologia , Estudos Longitudinais , Masculino , Proteínas de Membrana , Camundongos , Camundongos Transgênicos , Lipofuscinoses Ceroides Neuronais/complicações , Lipofuscinoses Ceroides Neuronais/patologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Tomografia por Emissão de Pósitrons , Análise de Componente Principal
12.
PLoS One ; 15(2): e0228222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074109

RESUMO

Genetically modified swine disease models are becoming increasingly important for studying molecular, physiological and pathological characteristics of human disorders. Given the limited history of these model systems, there remains a great need for proven molecular reagents in swine tissue. Here, to provide a resource for neurological models of disease, we validated antibodies by immunohistochemistry for use in examining central nervous system (CNS) markers in a recently developed miniswine model of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumor predisposition disorder stemming from mutations in NF1, a gene that encodes the Ras-GTPase activating protein neurofibromin. Patients classically present with benign neurofibromas throughout their bodies and can also present with neurological associated symptoms such as chronic pain, cognitive impairment, and behavioral abnormalities. As validated antibodies for immunohistochemistry applications are particularly difficult to find for swine models of neurological disease, we present immunostaining validation of antibodies implicated in glial inflammation (CD68), oligodendrocyte development (NG2, O4 and Olig2), and neuron differentiation and neurotransmission (doublecortin, GAD67, and tyrosine hydroxylase) by examining cellular localization and brain region specificity. Additionally, we confirm the utility of anti-GFAP, anti-Iba1, and anti-MBP antibodies, previously validated in swine, by testing their immunoreactivity across multiple brain regions in mutant NF1 samples. These immunostaining protocols for CNS markers provide a useful resource to the scientific community, furthering the utility of genetically modified miniswine for translational and clinical applications.


Assuntos
Biomarcadores/metabolismo , Neurofibromatose 1/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Linhagem da Célula , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas dos Microfilamentos/metabolismo , Microglia/citologia , Microglia/metabolismo , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Suínos
13.
Tob Control ; 29(5): 487-495, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31611425

RESUMO

OBJECTIVE: Policies raising the minimum legal sales age (MLSA) of tobacco products to 21 are commonly referred to as tobacco 21. This study sought to identify components of tobacco 21 policies and develop an instrument to examine policy language within 16 state laws adopted by July 2019. METHODS: The multistage tool development process began with a review of established literature and existing tobacco 21 policies. In a series of meetings, tobacco control experts identified key policy components used to develop an initial tool. After testing and revisions, the instrument was used to code the existing tobacco 21 state-level policies. Inter-rater reliability (κ=0.70) was measured and discrepancies were discussed until consensus was met. Policy component frequencies were reported by state. RESULTS: While all 16 states raised the MLSA to 21, the laws varied widely. Two laws omitted purchaser identification requirements. Fifteen laws mentioned enforcement would include inspections, but only three provided justification for conducting inspections. All 16 states provided a penalty structure for retailer/clerk violations, but penalties ranged considerably. Fourteen states required a tobacco retail licence, nine renewed annually. Six laws contained a military exemption, five were phased-in and 10 contained purchase, use or possession laws, which penalised youth. Four states introduced or expanded pre-emption of local tobacco control. CONCLUSIONS: The instrument developed is the first to examine policy components within state-level tobacco 21 laws. Policies that include negative components or omit positive components may not effectively prevent retailers from selling to youth, which could result in less effective laws.


Assuntos
Nicotiana , Política Pública/legislação & jurisprudência , Uso de Tabaco/legislação & jurisprudência , Humanos , Estados Unidos
14.
Mol Ther ; 27(10): 1836-1847, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31331814

RESUMO

CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken ß-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9.CB.hCLN6 into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 4-year-old non-human primates was safe, well tolerated, and led to efficient targeting throughout the brain and spinal cord. A single intracerebroventricular (i.c.v.) injection at post-natal day 1 in Cln6 mutant mice delivered scAAV9.CB.CLN6 directly into the CSF, and it prevented or drastically reduced all of the pathological hallmarks of Batten disease. Moreover, there were significant improvements in motor performance, learning and memory deficits, and survival in treated Cln6 mutant mice, extending survival from 15 months of age (untreated) to beyond 21 months of age (treated). Additionally, many parameters were similar to wild-type counterparts throughout the lifespan of the treated mice.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/psicologia , Lipofuscinoses Ceroides Neuronais/terapia , Actinas/genética , Animais , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Humanos , Infusões Intraventriculares , Injeções Espinhais , Aprendizagem/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Mutação , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Primatas , Regiões Promotoras Genéticas , Resultado do Tratamento
15.
Pain ; 160(11): 2473-2486, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31246731

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in NF1 (females only) pigs. Male NF1 pigs with tumors showed reduced sleep quality and increased resting, 2 health-related quality-of-life symptoms found to be comorbid in people with NF1 pain. We explore these phenotypes in relationship to suppression of the increased activity of the N-type voltage-gated calcium (CaV2.2) channel by pharmacological antagonism of phosphorylation of a regulatory protein-the collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin, and by targeting the interface between the α subunit of CaV2.2 and the accessory ß-subunits with small molecules. Our data support the use of NF1 pigs as a large animal model for studying NF1-associated pain and for understanding the pathophysiology of NF1. Our findings demonstrate the translational potential of 2 small molecules in reversing ion channel remodeling seen in NF1. Interfering with CaV2.2, a clinically validated target for pain management, might also be a promising therapeutic strategy for NF1-related pain management.


Assuntos
Genes da Neurofibromatose 1/fisiologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Qualidade de Vida , Animais , Canais de Cálcio Tipo N/genética , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/metabolismo , Masculino , Neurofibromina 1/genética , Neurônios/metabolismo , Dor/patologia , Suínos
16.
Mol Neurobiol ; 56(10): 6736-6755, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30915713

RESUMO

Collapsin response mediator proteins (CRMPs) are a family of ubiquitously expressed, homologous phosphoproteins best known for coordinating cytoskeletal formation and regulating cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. These functions are tightly regulated by post-translational modifications including phosphorylation, SUMOylation, oxidation, and O-GlcNAcylation. While CRMP2's physiological functions rely mostly on its non-phosphorylated state, dysregulation of CRMP2 phosphorylation and SUMOylation has been reported to be involved in the pathophysiology of multiple diseases including cancer, chronic pain, spinal cord injury, neurofibromatosis type 1, and others. Here, we provide a consolidated update on what is known about CRMP2 signaling and function, first focusing on axonal growth and neuronal polarity, then illustrating the link between dysregulated CRMP2 post-translational modifications and diseases. We additionally discuss the roles of CRMP2 in non-neuronal cells, both in the CNS and regions of the periphery. Finally, we offer thoughts on the therapeutic implications of modulating CRMP2 function in a variety of diseases.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Polaridade Celular , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Modelos Biológicos , Neurônios/patologia
17.
Nat Rev Neurol ; 15(3): 161-178, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30783219

RESUMO

Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten disease. Here, we provide an overview of the promising therapeutic avenues for Batten disease, highlighting current FDA-approved clinical trials and prospective future treatments.


Assuntos
Lipofuscinoses Ceroides Neuronais/terapia , Humanos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/etiologia , Tripeptidil-Peptidase 1
18.
Orphanet J Rare Dis ; 14(1): 19, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30665444

RESUMO

BACKGROUND: CLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression. RESULTS: A number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females. CONCLUSIONS: Thus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies.


Assuntos
Proteínas de Membrana/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Lipofuscinoses Ceroides Neuronais/genética , Doenças Raras/genética , Doenças Raras/metabolismo
19.
Neuronal Signal ; 3(2): NS20190001, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-32269836

RESUMO

CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

20.
PLoS One ; 13(8): e0201470, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30086172

RESUMO

CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten disease. Interestingly, we found that significant differences between Batten and non-disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten disease can influence potential biomarkers of the disease.


Assuntos
Variação Biológica da População , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Lipofuscinoses Ceroides Neuronais/diagnóstico , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Lipofuscinoses Ceroides Neuronais/sangue , Lipofuscinoses Ceroides Neuronais/genética
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