Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model

Gray‐Edwards, Heather L.; Regier, Debra S.; Shirley, Jamie L.; Randle, Ashley N.; Salibi, Nouha; Thomas, Sarah Ε.; Latour, Yvonne L.; Johnston, Jean M.; Golas, Gretchen; Maguire, Annie; Taylor, Amanda R.; Sorjonen, Donald C.; McCurdy, Victoria J.; Christopherson, Pete W.; Bradbury, Allison M.; Beyers, Ronald J.; Johnson, Aime K.; Brunson, Brandon L.; Cox, Nancy R.; Baker, Henry J.; Denney, Thomas S.; Sena‐Esteves, Miguel; Tifft, Cynthia J.; Martin, Douglas R.

doi:10.1016/j.ymthe.2017.01.009

Cited by 43 publications

(56 citation statements)

References 48 publications

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“…MRI data were acquired as previously described on a seven Tesla MAGNETOM scanner (Siemens Healthcare, Erlangen, Germany) from adult affected (n=3), carrier (n=2) and unaffected (n=4) cats as previously described [48]. A 32-channel head coil (Nova Medical, Boston, Mass.)…”

Section: Methodsmentioning

confidence: 99%

PEA15loss of function and defective cerebral development in the domestic cat

Graff

Cochran

Kaelin

et al. 2020

Preprint

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26Cerebral cortical size and organization are critical features of neurodevelopment and human 27 evolution, for which genetic investigation in model organisms can provide insight into 28 developmental mechanisms and the causes of cerebral malformations. However, some 29 abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory 30 mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in 31 domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a 32 smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in 33 PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 34 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, 35 present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral 36 defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% 37 average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian 38 and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is 39 substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the 40 cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. 41Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and 42 increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an 43 intracellular adapter protein, and suggesting an underlying pathophysiology in which increased 44 death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal 45 organization of neuronal layers and loss of white matter. Taken together, our work points to a new 46 role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic 47 species. 48 49 Summary 51Gyrification is the neurodevelopmental process in certain mammalian species during which the 52 cerebral cortex expands and folds resulting in the classic wrinkled appearance of the brain. 53Abnormalities in this process underlie many congenital malformations of the brain. However, 54 unlike many other human malformations, genetic insight into gyrification is not possible in 55 laboratory mice because rodents have a lissencephalic or smooth cerebral cortex. We identified 56 a mutation in domestic cats that likely causes failure of the cerebral cortex to expand and fold 57properly, and discovered that the mutation impairs production of a protein, PEA15 58(phosphoprotein expressed in astrocytes-15), involved in intracellular signaling. Affected cats 59 have profound abnormalities in brain development, with minimal changes in their superficial 60 behavior and neurologic function. Additional studies of tissue and cultured cells from affected 61 animals suggest a pathophysiologic mechani...

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Section: Methodsmentioning

confidence: 99%

PEA15loss of function and defective cerebral development in the domestic cat

Graff

Cochran

Kaelin

et al. 2020

Preprint

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“…In addition to humans, it is described in cats [2][3][4][5][6][7][8], dogs [9][10][11][12], strategies for lysosomal storage diseases in humans [57]. Gene therapy certainly provides the most promising results when applied early enough but has predominantly been studied in animal models yet so far [49,50,[58][59][60][61][62]. Despite characterization of several animal models and detailed studies in human patients, various aspects of the pathogenesis of murine G M1 -gangliosidosis, particularly regarding functional aspects, axonal damage and lack of demyelination partly remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

“…All mouse models developed lesions characteristic of G M1 -gangliosidosis [22][23][24]. Furthermore, feline models have been utilized in therapy trials, particularly gene therapy [49,50]. The mouse models were classified as [23] or compared with [22,24] the infantile or juvenile form of G M1 -gangliosidosis despite the late onset of the disease.…”

Section: Introductionmentioning

confidence: 99%

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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“…[10] Thebacterial lacZgene produces the enzyme b-galactosidase (b-gal) and has been historically important as ag ene reporter. [11] Ty pically,i nv ivo detection of lacZh as been accomplished using colorimetric assays that require the organism be sacrificed and the tissues of interest be stained for the presence of b-gal. To overcome this limitation, we designed aseries of b-gal activated MR contrast agents employing a q modulation mechanism that successfully detected gene expression in vitro and in Xenopus laevis.…”

Section: Introductionmentioning

confidence: 99%

“…Thec hallenge in achieving intramolecular coordination is to impart enough flexibility to the linker to create asituation where the carboxylate coordination is more favorable than either carbamate or intermolecular CO 3 2À coordination. In the presence of the enzyme,b oth the interand intramolecular mechanisms self-immolate to the identical product (11), which was independently synthesized and characterized in this study.…”

mentioning

confidence: 99%

Self‐Immolative Activation of β‐Galactosidase‐Responsive Probes for In Vivo MR Imaging in Mouse Models

et al. 2019

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Our lab has developed a new series of self‐immolative MR agents for the rapid detection of enzyme activity in mouse models expressing β‐galactosidase (β‐gal). We investigated two molecular architectures to create agents that detect β‐gal activity by modulating the coordination of water to GdIII. The first is an intermolecular approach, wherein we designed several structural isomers to maximize coordination of endogenous carbonate ions. The second involves an intramolecular mechanism for q modulation. We incorporated a pendant coordinating carboxylate ligand with a 2, 4, 6, or 8 carbon linker to saturate ligand coordination to the GdIII ion. This renders the agent ineffective. We show that one agent in particular (6‐C pendant carboxylate) is an extremely effective MR reporter for the detection of enzyme activity in a mouse model expressing β‐gal.

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Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model

Cited by 43 publications

References 48 publications

PEA15loss of function and defective cerebral development in the domestic cat

PEA15loss of function and defective cerebral development in the domestic cat

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Self‐Immolative Activation of β‐Galactosidase‐Responsive Probes for In Vivo MR Imaging in Mouse Models

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