The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice

Whitmore, C.; Fernández-Fuente, Marta; Booler, Helen; Parr, Christian; Kavishwar, Manoli; Ashraf, Attia; Lacey, Erica; Kim, Jihee; Terry, Rebecca; Ackroyd, M.R.; Wells, Kim E.; Muntoni, Francesco; Wells, Dominic J.; Brown, Susan C.

doi:10.1093/hmg/ddt577

Cited by 34 publications

(29 citation statements)

References 67 publications

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“…LARGE transgenic mice with a normal background tend to exhibit normal development and muscle histology; however, the aged LARGE transgenic mice show an increase in susceptibility to contraction-induced injury and a 30% decline in force generation when compared with age-matched controls (Brockington et al, 2010). More recently, Dr. Brown's group further reported that contrary to expectation, transgenic expression of LARGE in a dystrophic mouse with FKRP mutations resulted in a worsening of the muscle pathology, implying that any future strategies based upon LARGE upregulation require careful management (Whitmore et al, 2013). These results are apparently in contradiction to the observation from the current study, which showed a clear pathological benefit from the LARGE-induced functional glycosylation of a-DG in FKRP mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Vannoy

Keramaris

et al. 2014

Human Gene Therapy Methods

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Multiple genes (e.g., POMT1, POMT2, POMGnT1, ISPD, GTDC2, B3GALNT2, FKTN, FKRP, and LARGE) are known to be involved in the glycosylation pathway of a-dystroglycan (a-DG). Mutations of these genes result in muscular dystrophies with wide phenotypic variability. Abnormal glycosylation of a-DG with decreased extracellular ligand binding activity is a common biochemical feature of these genetic diseases. While it is known that LARGE overexpression can compensate for defects in a few aforementioned genes, it is unclear whether it can also rescue defects in FKRP function. We examined adeno-associated virus (AAV)-mediated LARGE or FKRP overexpression in two dystrophic mouse models with loss-of-function mutations: (1) Large myd (LARGE gene) and (2) FKRP P448L (FKRP gene). The results agree with previous findings that overexpression of LARGE can ameliorate the dystrophic phenotypes of Large myd mice. In addition, LARGE overexpression in the FKRP P448L mice effectively generated functional glycosylation (hyperglycosylation) of a-DG and improved dystrophic pathologies in treated muscles. Conversely, FKRP transgene overexpression failed to rescue the defect in glycosylation and improve the phenotypes of the Large myd mice. Our findings suggest that AAVmediated LARGE gene therapy may still be a viable therapeutic strategy for dystroglycanopathies with FKRP deficiency.

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Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Vannoy

Keramaris

et al. 2014

Human Gene Therapy Methods

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“…Numerous emerging therapeutic questions in the CMD to be addressed in the shorter term were discussed and led to the following conclusions:

In the dystroglycanopathies prednisone seems to be ready for a clinical trial, and should be tested in fukutin and FKRP mouse models. Further questions to address are the applicability of LARGE upregulation, as well as its limitations since its transgenic upregulation on disease backgrounds has been shown to be deleterious [58,59], modeling cardiac disease in the mouse model, and the question whether the CNS diseases can be influenced by therapeutic interventions. The applicability of AAV-mediated gene transfer therapy could be assessed in various genetic models.

For LAMA2 -CMD, the critical question remaining unanswered is to identify the different driving mechanisms at different stages of the disease.

…”

Section: Translational Link To the Clinicmentioning

confidence: 99%

“…Further questions to address are the applicability of LARGE upregulation, as well as its limitations since its transgenic upregulation on disease backgrounds has been shown to be deleterious [58,59], modeling cardiac disease in the mouse model, and the question whether the CNS diseases can be influenced by therapeutic interventions. The applicability of AAV-mediated gene transfer therapy could be assessed in various genetic models.…”

Section: Translational Link To the Clinicmentioning

confidence: 99%

212th ENMC International Workshop:

Durbeej

Allamand

Bonaldo³

et al. 2016

Neuromuscular Disorders

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“…Overexpression of LARGE via an adenoviral vector is capable of hyperglycosylating skeletal muscle α-DG in vivo [19]. Although LARGE overexpression by transgenic approach exacerbates muscular dystrophy in FKRP knock-down mice [20] and fukutin knockout mice [21] thought to be caused by inhibition of regeneration from satellite cells, we have shown that LARGE expression ameliorates muscular dystrophy in LARGE mutant and POMGnT1 knockout mice when delivered systemically by an adeno-associated viral vector 9 (AAV9) after birth [22]. Furthermore, AAV-mediated expression of LARGE, fukutin-related protein, or B4GALNT2 (GALGT2) ameliorates muscular dystrophic phenotype in FKRP mutant mice [23,24,25] and in a mouse model bearing a pathogenic human FKRP mutation [26].…”

Section: Introductionmentioning

confidence: 99%

Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder

Liu

Bampoe

et al. 2016

Genes

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Patients with type II lissencephaly, a neuronal migration disorder with ectopic neurons, suffer from severe mental retardation, including learning deficits. There is no effective therapy to prevent or correct the formation of neuronal ectopia, which is presumed to cause cognitive deficits. We hypothesized that learning deficits were not solely caused by neuronal ectopia and that postnatal gene therapy could improve learning without correcting the neuronal ectopia formed during fetal development. To test this hypothesis, we evaluated spatial learning of cerebral cortex-specific protein O-mannosyltransferase 2 (POMT2, an enzyme required for O-mannosyl glycosylation) knockout mice and compared to the knockout mice that were injected with an adeno-associated viral vector (AAV) encoding POMT2 into the postnatal brains with Barnes maze. The data showed that the knockout mice exhibited reduced glycosylation in the cerebral cortex, reduced dendritic spine density on CA1 neurons, and increased latency to the target hole in the Barnes maze, indicating learning deficits. Postnatal gene therapy restored functional glycosylation, rescued dendritic spine defects, and improved performance on the Barnes maze by the knockout mice even though neuronal ectopia was not corrected. These results indicate that postnatal gene therapy improves spatial learning despite the presence of neuronal ectopia.

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The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice

Cited by 34 publications

References 67 publications

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

212th ENMC International Workshop:

Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder

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