Intracerebral cell transplantation therapy for murine GM1 gangliosidosis

Sawada, Tomo; Tanaka, Akemi; Higaki, Kazutaka; Takamura, Ayumi; Nanba, Eiji; Seto, Toshiyuki; Maeda, Masayuki; Yamaguchi, Etsuko; Matsuda, Junichiro; Yamano, Tunekazu

doi:10.1016/j.braindev.2008.11.004

Cited by 12 publications

(9 citation statements)

References 44 publications

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“…Stem cell transplantation (SCT) early in the course of disease may ameliorate symptoms in GM1 gangliosidosis (Sawada et al, 2009), although for optimal benefit, like Krabbe disease, the transplant would need to be undertaken in the first few weeks of life; a strong argument for universal newborn screening for GM1 disease. Although it could be successfully utilized in GM1 gangliosidosis and may reduce visceral features, the long-term correction of neurological symptoms is less likely.…”

Section: Stem Cell Transplantationmentioning

confidence: 99%

GM1 Gangliosidosis—A Mini-Review

et al. 2021

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GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).

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Section: Stem Cell Transplantationmentioning

confidence: 99%

GM1 Gangliosidosis—A Mini-Review

et al. 2021

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“…[187][188][189] Transplantation of fetal brain cells (FBC) or bonemarrow-derived mesenchymal stem cells (MSC) from mice over-expressing β-gal, was also able to effectively treat neurological disease short term for β-gal -/mice. 84 However, short-term efficacy did not result in long-term benefit. Grafted cells were not detected at six months post treatment for mice administered MSCs, or a mixture of MSCs and FBCs, and FBC number significantly decreased over time.…”

Section: Stem Cell Transplantationmentioning

confidence: 99%

“…stem cell transplantation, [83][84][85][86] enzyme replacement therapy (ERT), 56,[87][88][89][90] and treatment with pharmacological chaperones, 55,[91][92][93][94][95][96][97][98] while substrate reduction is mediated through inhibition of ceramide glucosyltransferase, 30,[99][100][101][102] the enzyme that catalyzes the first committed step of GSL biosynthesis. For treatment of symptomatic individuals, substrate reduction therapy relies on residual β-gal activity to remove ganglioside that has already accumulated.…”

Section: Rha Et Almentioning

confidence: 99%

“…There are no current effective FDA-approved treatments for GM1, though advances in gene therapy are rapidly gaining traction with human clinical trials underway. Targeted research approaches for the treatment of GM1 typically align with one of the following areas: substrate reduction therapy (SRT), 30,[99][100][101][102]167,168 enzyme enhancement therapy (EET), 55,91,93,94,[169][170][171] stem cell transplantation, [83][84][85][86] enzyme replacement therapy (ERT), 56,87,89,90 or gene therapy 48,57,[60][61][62][63][64] (Figure 3). These therapeutic approaches aim to slow clinical progression, increase quality of life, and extend life expectancy through reduction of GM1 ganglioside content, enhancement of residual β-gal activity, or introduction of an exogenous active β-gal cDNA or enzyme.…”

Section: Managementmentioning

confidence: 99%

“…Grafted cells were not detected at six months post treatment for mice administered MSCs, or a mixture of MSCs and FBCs, and FBC number significantly decreased over time. 84…”

Section: Stem Cell Transplantationmentioning

confidence: 99%

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GM1 Gangliosidosis: Mechanisms and Management

Rha¹,

Maguire²,

Martin³

2021

TACG

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The lysosomal storage disorder, GM1 gangliosidosis (GM1), is a neurodegenerative condition resulting from deficiency of the enzyme β-galactosidase (β-gal). Mutation of the GLB1 gene, which codes for β-gal, prevents cleavage of the terminal β-1,4-linked galactose residue from GM1 ganglioside. Subsequent accumulation of GM1 ganglioside and other substrates in the lysosome impairs cell physiology and precipitates dysfunction of the nervous system. Beyond palliative and supportive care, no FDA-approved treatments exist for GM1 patients. Researchers are critically evaluating the efficacy of substrate reduction therapy, pharmacological chaperones, enzyme replacement therapy, stem cell transplantation, and gene therapy for GM1. A Phase I/II clinical trial for GM1 children is ongoing to evaluate the safety and efficacy of adeno-associated virus-mediated GLB1 delivery by intravenous injection, providing patients and families with hope for the future.

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