Towards an understanding of Angelman syndrome in mice studies

Yang, Xin

doi:10.1002/jnr.24576

Cited by 11 publications

(10 citation statements)

References 125 publications

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“… 55 , 56 , 57 Emerging therapies which restore neural UBE3A expression have the potential to directly modify the pathogenic disease process in AS. 12 In rodent models of AS, 11 successes in restoring neural UBE3A expression using antisense oligonucleotides 13 and topoisomerase inhibitors 14 , 15 have been achieved, and have fast‐approaching potential for transition to clinical therapies. Direct measures of UBE3A expression in these models were demonstrated through direct assays of neuronal tissue; behavioral measures provided a less robust response.…”

Section: Discussionmentioning

confidence: 99%

“…Table S2. Spectral power in the delta (2-4 Hz), theta (5-7 Hz), alpha (8)(9)(10)(11)(12), and beta (13-30 Hz) frequency bands was used to model cognitive function. The standardized coefficient estimates (β AE SE) and P-values for the spectral predictors in each model are shown, with P-values that pass Bonferroni correction (P < 0.00714 for 7 tests) indicated in bold.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“… 6 , 7 , 8 AS is caused by loss of function of the maternally inherited and paternally imprinted ubiquitin‐protein ligase UBE3A gene in neurons. 9 , 10 Targeted disease‐modifying treatments to reinstate UBE3A expression in neurons are under development, 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 and a robust, easily obtained and quantifiable biomarker that reliably assays disease severity is critical to an assessment of efficacy in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Delta power robustly predicts cognitive function in Angelman syndrome

Ostrowski

Spencer

Bird

et al. 2021

Ann Clin Transl Neurol

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Objective: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene in neurons. Promising disease-modifying treatments to reinstate UBE3A expression are under development and an early measure of treatment response is critical to their deployment in clinical trials. Increased delta power in EEG recordings, reflecting abnormal neuronal synchrony, occurs in AS across species and correlates with genotype. Whether delta power provides a reliable biomarker for clinical symptoms remains unknown. Methods: We analyzed combined EEG recordings and developmental assessments in a large cohort of individuals with AS (N = 82 subjects, 133 combined EEG and cognitive assessments, 1.08-28.16 years; 32F) and evaluated delta power as a biomarker for cognitive function, as measured by the Bayley Cognitive Score. We examined the robustness of this biomarker to varying states of consciousness, recording techniques and analysis procedures. Results: Delta power predicted the Bayley Scale cognitive score (P < 10 −5 , R 2 = 0.9374) after controlling for age (P < 10 −24 ), genotype: age (P < 10 −11 ), and repeat assessments (P < 10 −8 ), with the excellent fit on cross validation (R 2 = 0.95). There were no differences in model performance across states of consciousness or bipolar versus average montages (ΔAIC < 2). Models using raw data excluding frontal channels outperformed other models (ΔAIC > 4) and predicted performance in expressive (P = 0.0209) and receptive communication (P < 10 −3 ) and fine motor skills (P < 10 −4 ). Interpretation: Delta power is a simple, direct measure of neuronal activity that reliably correlates with cognitive function in AS. This electrophysiological biomarker offers an objective, clinically relevant endpoint for treatment response in emerging clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Conflict Of Interestmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delta power robustly predicts cognitive function in Angelman syndrome

Ostrowski

Spencer

Bird

et al. 2021

Ann Clin Transl Neurol

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“…Except for approaches that aim at unsilencing the paternal allele, therefore restoring the genetic defect, which could in principle repair all deficits, but are still underdeveloped and debated [Tsagkaris et al, 2020], to our knowledge, comprehensive alternative therapeutic agents that broadly ameliorate cognitive, motor and neurological impairments have been lacking [Jamal et al, 2017; Meng et al, 2013; Sun et al, 2016; Yang, 2019]. Our findings suggest that it may be possible to design drug targets against the CIM6P/IGF‐2R that can broadly treat AS symptoms and could be readily developed for clinical testing.…”

Section: Discussionmentioning

confidence: 99%

CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

et al. 2020

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Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin‐like growth factor 2 (IGF‐2) and mannose‐6‐phosphate (M6P), ligands of two independent binding sites of the cation‐independent M6P/IGF‐2 receptor (CIM6P/IGF‐2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF‐2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y‐maze. IGF‐2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF‐2R is a promising approach for developing novel therapeutics for AS. Lay Summary There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am−/p+, in this study we show that systemic administration of ligands of the cation independent mannose‐6‐phosphate receptor, also known as insulin‐like growth factor 2 receptor (CIM6P/IGF‐2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF‐2R may represent novel, potential therapeutic targets for AS.

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“…In 1965, the British Doctor Harry Angelman first described AS and named it after his surname. The frequency of this condition is estimated to be 1 in 15,000 individuals ( 2 ). AS is a maternally inherited neurodevelopmental genetic disease associated with chromosomal abnormality at the 15q11-q13 genetic region ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Two siblings suffering from Angelman Syndrome with a novel c.1146T>G mutation in UBE3A: A case report

Liu

Sun

et al. 2022

Biomed Rep

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Angelman syndrome (AS) is an autosomal dominant neurodevelopmental genetic disease with maternal imprint, which is associated with the presence of the abnormal chromosome 15q11-q13, and the loss of maternal specific expression of ubiquitin-protein ligase E3A (UBE3A). The expression levels of UBE3A depend on the parental origin and exhibit tissue specificity. In normal brain tissues, the maternal UBE3A gene is actively expressed, whereas the paternal UBE3A gene is not. In total, ~85% of pediatric patients with AS present with epilepsy within their 3rd year of life. This condition is usually difficult to control with medical treatment. An 8-year-old female visited the Affiliated Hospital of Jining Medical University due to frequent epilepsy. Her clinical manifestations included specific facial features, moderate mental retardation and frequent seizures. It was interesting to note that her 15-year-old sister exhibited similar clinical manifestations to those of AS. The results of the electroencephalogram and the imaging examinations were also in line with the characteristics of AS. In order to further clarify the diagnosis, all the suspected genes in her sister and in their parents were sequenced. The multiplex ligation-dependent probe amplification project of the Angel/chubby and copy number variation (CNV) sequencing were assessed concomitantly to identify the pathogenic genes responsible for the development of AS. The latter occurs due to the missense mutation c.1146T>G, which results in asparagine replacement by lysine at position 382 (p.Asn382Lys) in exon 7. This amino acid change affects the normal expression of UBE3A; the mutation is a novel mutation, which, to the best of our knowledge, has not been previously reported. Relevant large fragments of mutations and methylation abnormalities were not found in the associated genes. The data further revealed absence of 25-bp repeat mutations at the shear mutation site of exon 1 of the small nuclear ribonucleoprotein polypeptide N gene in the subjects examined. No suspected CNV was found following analysis.

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Towards an understanding of Angelman syndrome in mice studies

Cited by 11 publications

References 125 publications

Delta power robustly predicts cognitive function in Angelman syndrome

Delta power robustly predicts cognitive function in Angelman syndrome

CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

Two siblings suffering from Angelman Syndrome with a novel c.1146T>G mutation in UBE3A: A case report

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