Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis

Carias, Karin Vanessa; Wevrick, Rachel

doi:10.1016/j.omtm.2019.03.001

Cited by 24 publications

(16 citation statements)

References 171 publications

(220 reference statements)

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“…The vast majority of human patients are affected by a disruption of these genes in addition to loss of the functionally elusive non-protein coding RNAs and transcripts. The existing mouse models led to a better understanding of the underlying pathophysiological mechanisms and some were tested within a number of ongoing pharmacological trials in search of therapeutic agents [ 150 ].…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

Kummerfeld

Raabe

Brosius

et al. 2021

IJMS

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Prader-Willi syndrome (PWS) is a neurogenetic multifactorial disorder caused by the deletion or inactivation of paternally imprinted genes on human chromosome 15q11-q13. The affected homologous locus is on mouse chromosome 7C. The positional conservation and organization of genes including the imprinting pattern between mice and men implies similar physiological functions of this locus. Therefore, considerable efforts to recreate the pathogenesis of PWS have been accomplished in mouse models. We provide a summary of different mouse models that were generated for the analysis of PWS and discuss their impact on our current understanding of corresponding genes, their putative functions and the pathogenesis of PWS. Murine models of PWS unveiled the contribution of each affected gene to this multi-facetted disease, and also enabled the establishment of the minimal critical genomic region (PWScr) responsible for core symptoms, highlighting the importance of non-protein coding genes in the PWS locus. Although the underlying disease-causing mechanisms of PWS remain widely unresolved and existing mouse models do not fully capture the entire spectrum of the human PWS disorder, continuous improvements of genetically engineered mouse models have proven to be very powerful and valuable tools in PWS research.

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Section: Discussionmentioning

confidence: 99%

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

Kummerfeld

Raabe

Brosius

et al. 2021

IJMS

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“…In recent years, a number of innovative therapeutic approaches have been developed, notably for PWS and for patients with alterations of the melanocortin pathway upstream of the MC4R receptor (68,69). Pharmaceutical interventions reported in NCT clinical trials for weight loss in syndromic and monogenic obesities are described in Table 1, with ongoing and completed studies.…”

Section: Toward Therapeutic Innovations In Genetic Obesitymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

Poitou

Mosbah

Clément

2020

European Journal of Endocrinology

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Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome, and, ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

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“…On the other hand, generation of Magel2 tm1Stw mice was achieved by replacing the Magel2 gene by a fused gene that encodes the N terminal part of the Magel2 gene fused with Beta-Gal gene, resulting in a Magel2/B-Gal fused protein. Magel2 tm1Stw displays reduced signs of anxiety, lack a preference for social novelty, and impaired learning ability [ 56 ]. Distinct and overlapping symptoms of PWS and SYS in humans, genetic causes [ 57 , 58 ], and the two different Magel2 KO mice are highlighted in Fig.…”

Section: Prader-willi and Schaaf-yang Syndromes And The Role Of Oxyto...mentioning

confidence: 99%

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

et al. 2022

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The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

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Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis

Cited by 24 publications

References 171 publications

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

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