Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Adhikari, Anna; Copping, Nycole A; Beegle, Julie R.; Cameron, David L; Deng, Peter; O’Geen, Henriette; Segal, David J.; Fink, Kyle D.; Silverman, Jill L.; Anderson, Joseph S.

doi:10.1093/hmg/ddab104

Cited by 32 publications

(54 citation statements)

References 64 publications

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“…Although our study returned mostly negative results regarding the potential for IGF-2 to improve behavioral deficits in AS, our findings are nevertheless important to disseminate, as they contrast other recent data [ 47 ]. While we were aiming to corroborate the previous reports of IGF-2 efficacy, as inter-laboratory reproducibility is a long-standing goal of ours, we did establish strong reproducibility with other rat studies [ 16 , 71 – 73 ], EEG and sleep studies [ 72 , 74 – 77 , 82 ], and other genetic mutant mouse models of neurodevelopmental disorders [ 51 , 56 , 78 ]. Furthermore, we did reproduce a number of the Ube3a mat−/pat+ mouse phenotypes observed by Cruz et al specifically hypolocomotion, fewer marbles buried, and poor rotarod performance [ 47 ].…”

Section: Discussionsupporting

confidence: 57%

“…One potential explanation as to why we observed effects on EEG power spectral density (PSD) but no changes in behavioral performance is that the increase in delta power may not have substantial behavioral significance. However, we find this explanation unlikely in light of recent evidence from our laboratory illustrating reductions delta power with concomitant behavioral improvements [ 74 ] and a new report in humans with Angelman Syndrome [ 70 ]. A more likely explanation for the present data is that the IGF-2-induced delta power reduction was sub-threshold for behavioral change.…”

Section: Discussionmentioning

confidence: 61%

“…AS model mice on the traditional B6J background do not exhibit spontaneous seizures nor susceptibility to audiogenic seizures [ 69 ]. Because the 129 strain has a 70% reduction in corpus callosum volume which adds to their seizure susceptibility [ 77 , 81 , 82 ], and sensory-dependent audiogenic seizures are triggered by divergent neural circuitry compared to chemo-induction [ 74 ], we utilized the B6J background with a chemo-convulsant.…”

Section: Discussionmentioning

confidence: 99%

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Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

et al. 2021

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Background Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. Methods We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. Results Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. Limitations The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. Conclusions Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

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“…AS is caused by dysfunction of maternal ubiquitin protein ligase E3A (UBE3A), typically from a de novo deletion in the 15q11-q13 region ( Albrecht et al, 1997 ). Restoring functional UBE3A is seemingly possible by innovative gene therapy approaches, including antisense oligonucleotides ( Meng et al, 2015 ), viral vector delivery ( Daily et al, 2011 ), artificial transcription factors ( Bailus et al, 2016 ), stem cell-mediated therapies ( Adhikari et al, 2021 ), and the cutting edge Cas9 ( Wolter et al, 2020 ). Gene replacement therapy is therefore on the horizon for AS; and indeed, two clinical trials using “gene therapy-like” antisense oligonucleotide interventions began recruitment in 2020 (GeneTx NCT04259281; Roche NCT04428281).…”

Section: Introductionmentioning

confidence: 99%

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in theUbe3aDeletion Rat Model of Angelman Syndrome

et al. 2021

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Angelman Syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50-kHz ultrasonic emissions in the Ube3a mat-/pat+ rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3a mat-/pat+ rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying long-term potentiation deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared to currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS. Significance StatementAngelman Syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study utilized a recently developed rat model of AS to delineate disease-relevant outcome measures in order to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes including overabundant laughter-like vocalizations, reduced hippocampal longterm potentiation, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS and the outcome metrics reported herein will be central to the therapeutic pipeline.

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“…DigiGait avoids many of these pitfalls and has been to be a versatile tool, sensitive to various treatments, and has a record of use as a strong longitudinal/repeat testing outcome measure (Adhikari et al, 2021;Akula et al 2020;Hansen & Pulst, 2013;Orfany et al, 2020;Zhan et al, 2019). Treadmill gait analysis using ventral imaging, such as DigiGait and the CatWalk, allow for unhindered access to the ambulating mouse to detect more nuanced and fine-grained phenotypes (Lei et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

Petkova

Duis

Silverman

2021

Preprint

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Angelman Syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, and walking and balance disorders. Recently, motor ability became an interesting outcome measure in AS, as it is broad including ataxia, hypotonia, delayed and abnormal walking and postural movements and affects nearly every individual with AS. We predict that gait presents a strong opportunity for rigorous, reliable, and quantitative metrics with direct translation to evaluate pharmacological, dietary, and genetic therapies. Numerous motoric deficits have been identified clinically. In this study, we used an innovative, automated gait analysis as well as gold standard motor behavioral assays to further delineate components of motor, coordination, balance, and gait impairments in an AS mouse model across development. Our study demonstrated marked global motoric deficits in AS mice, corroborating many previous reports. Uniquely, this is the first report of nuanced and pertinent aberrations in quantitative spatial and temporal components of gait between AS and wildtype littermate controls, that are analogous in AS individuals. These metrics were followed longitudinally to observe the progression of maladaptive gait in AS, a clinical phenotype. This has not been reported previously and contributes a substantial novel metric for therapeutic development. Taken together, these findings demonstrate the robust translational value in the study of nuanced motor outcomes, i.e., gait, for AS, as well as similar genetic syndromes, in the endeavor of therapeutic screening.

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Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Cited by 32 publications

References 64 publications

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in theUbe3aDeletion Rat Model of Angelman Syndrome

Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

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