Gene induction for the treatment of methylmalonic aciduria

Hu, Ruimei; Buck, Nicole E.; Khaniani, Mahmoud Shekari; Wood, Leonie R.; Wardan, Hady; Benoist, J.-F.; Li, Lingli; Vadolas, Jim; Sarsero, Joseph P.; Ioannou, Panos; Peters, Heidi

doi:10.1002/jgm.1297

Cited by 5 publications

(3 citation statements)

References 19 publications

(23 reference statements)

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“…Development of cellular genomic reporter assays for MMA have allowed the identification of compounds that have the potential of modulating the expression of MCM which provides new approachs for the treatment of methylmalonic aciduria [20], [21].…”

Section: Introductionmentioning

confidence: 99%

Mouse Models for Methylmalonic Aciduria

et al. 2012

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Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of methylmalonyl-CoA mutase (MCM). MMA is associated with significant morbidity and mortality, thus therapies are necessary to help improve quality of life and prevent renal and neurological complications. Transgenic mice carrying an intact human MCM locus have been produced. Four separate transgenic lines were established and characterised as carrying two, four, five or six copies of the transgene in a single integration site. Transgenic mice from the 2-copy line were crossed with heterozygous knockout MCM mice to generate mice hemizygous for the human transgene on a homozygous knockout background. Partial rescue of the uniform neonatal lethality seen in homozygous knockout mice was observed. These rescued mice were significantly smaller than control littermates (mice with mouse MCM gene). Biochemically, these partial rescue mice exhibited elevated methylmalonic acid levels in urine, plasma, kidney, liver and brain tissue. Acylcarnitine analysis of blood spots revealed elevated propionylcarnitine levels. Analysis of mRNA expression confirms the human transgene is expressed at higher levels than observed for the wild type, with highest expression in the kidney followed closely by brain and liver. Partial rescue mouse fibroblast cultures had only 20% of the wild type MCM enzyme activity. It is anticipated that this humanised partial rescue mouse model of MMA will enable evaluation of long-term pathophysiological effects of elevated methylmalonic acid levels and be a valuable model for the investigation of therapeutic strategies, such as cell transplantation.

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Section: Introductionmentioning

confidence: 99%

Mouse Models for Methylmalonic Aciduria

et al. 2012

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“…The quantity and integrity of purified RNA were assessed photometrically using NanoDrop ® ND-1000 Spectrophotometer (Thermo Scientific, USA) and observation of 28S and 18S ribosomal RNA bands after electrophoresis on 0.8% agarose gel, respectively. Finally, complementary DNA (cDNA) was synthesized from 1 µg of DNase I-treated total RNA using RevertAid™ First Strand cDNA Synthesis Kit (Fermentas, Canada) with random hexamer primer following the manufacturer's protocol and published method (21).…”

Section: Rna Extraction and Cdna Synthesismentioning

confidence: 99%

Supplementation with omega fatty acids increases the mRNA expression level of PLA2G4A in patients with gastric cancer

Bazhan

Khaniani

2018

J. Gastrointest. Oncol

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Background: Many lines of evidence suggest that arachidonic acid (AA)-based eicosanoid signaling pathway involved in development and progression of human cancers. Cytosolic phospholipase A2-α (cPLA2α) encoded by the PLA2G4A gene acts as an upstream regulator of eicosanoid signaling pathway through providing intracellular AA. The current study aimed to evaluate the effect of omega fatty acids on mRNA expression level of PLA2G4A in patients with gastric cancer (GC) and to assess the possible relation between its expression and clinicopathological features. Methods: According to treatment strategy, 34 chemotherapy-naive patients were randomly divided into two groups including, treatment group I (17 subjects received cisplatin alone) and treatment group II (17 individuals received cisplatin plus omega fatty acids) in a double-blind manner. The gastric biopsies specimens were taken from subjects before and after treatment and then mRNA expression level of PLA2G4A was evaluated by quantitative real-time PCR procedure. Results: The expression of the PLA2G4A gene at the protein level in the gastric biopsies samples was also determined by immunohistochemistry. Our findings revealed a significantly up-regulated expression of PLA2G4A mRNA in treatment group II after receiving cisplatin plus omega fatty acid compared to before treatment (P=0.003). In treatment group I, there was no significant difference in mRNA expression levels of PLA2G4A before and after treatment (P=0.790). We also found that mRNA expression of PLA2G4A in treatment group II was significantly associated with tumor size (P=0.007) and familial history (P=0.006). Conclusions: This study provides evidence that supplementation with omega fatty acids increases the mRNA expression level of PLA2G4A in patients with GC and may be crucial in guarding the cell from transformation and carcinogenesis.

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“…Over the years, numerous publications have detailed various strategies to treat MMUT deficiency. These include systemic lentiviral delivery, 34,35 adenoviral gene therapy, 36 mRNA read-through agents, 37,38 MMUT gene induction, 39 antioxidant treatment, 40 and cobalamin administration (OHCbl). 41 While these studies are, in aggregate, promising, the current review will focus on three new therapeutic approaches that have received investigational new drug approval by the Food and Drug Administration (FDA).…”

Section: Introductionmentioning

confidence: 99%

Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia

Venturoni

Venditti

2022

J of Inher Metab Disea

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Hereditary methylmalonic acidemia (MMA) caused by deficiency of the enzyme methylmalonyl-CoA mutase (MMUT) is a relatively common and severe organic acidemia. The recalcitrant nature of the condition to conventional dietary and medical management has led to the use of elective liver and combined liver-kidney transplantation in some patients. However, liver transplantation is intrinsically limited by organ availability, the risks of surgery, procedural and life-long management costs, transplant comorbidities, and a remaining underlying risk of complications related to MMA despite transplantation. Here, we review pre-clinical studies that present alternative approaches to solid organ transplantation as a treatment for MMUT MMA, including adeno-associated viral gene addition therapy, mRNA therapy, and genome editing, with and without nuclease enhancement.

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Gene induction for the treatment of methylmalonic aciduria

Abstract: This assay has the potential of being used in high-throughput screening of chemical libraries for the identification of novel compounds that specifically modulate the expression of MCM.

Cited by 5 publications

References 19 publications

Mouse Models for Methylmalonic Aciduria

Mouse Models for Methylmalonic Aciduria

Supplementation with omega fatty acids increases the mRNA expression level of PLA2G4A in patients with gastric cancer

Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia

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