Treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia

Rivera-Barahona, Ana; Alonso-Barroso, Esmeralda; Pérez, Belén; Murphy, Michael P.; Richard, Eva; Desviat, Lourdes R.

doi:10.1016/j.ymgme.2017.07.009

Cited by 31 publications

(29 citation statements)

References 44 publications

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“…Due to the low mortality rate observed in PA hypomorphic mice, these studies were not powered to detect differences in survival. Similarly, compared to previous publications 38 , 39 , we observed a milder mitochondrial dysfunction in PA hypomorphic mice (Supplementary Fig. 6 ).…”

Section: Discussionsupporting

confidence: 88%

Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

et al. 2020

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Propionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders.

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Section: Discussionsupporting

confidence: 88%

Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

et al. 2020

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“…Half of the animals of each group received the mitochondrial antioxidant MitoQ (200 µM) in the drinking water for the same period. The dose of MitoQ was based on previous data [15]. MitoQ was provided by MP Murphy from Medical Research Council Mitochondrial Biology Unit, Cambridge BioMedical Campus, Cambridge, UK.…”

Section: Animal Modelmentioning

confidence: 99%

The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats

Jiménez-González

Marín-Royo

Jurado-López

et al. 2020

Cells

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The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial 18-FDG uptake reduction, and mitochondrial lipid remodeling in HFD rats. It also ameliorated cardiac mitochondrial protein level changes observed in HFD: reductions in fumarate hydratase, complex I and II, as well as increases in mitofusin 1 (MFN1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and cyclophilin F (cycloF). In vitro, MitoQ prevented oxidative stress and ameliorated alterations in mitochondrial proteins observed in palmitic acid (PA)-stimulated cardiac myoblasts: increases in carnitine palmitoyltransferase 1A, cycloF, and cytochrome C. PA induced phosphorylation of extracellular signal-regulated kinases and nuclear factor-κB p65. Therefore, the data show the beneficial effects of MitoQ in the cardiac damage induced by obesity and suggests a crosstalk between lipotoxicity and mitochondrial oxidative stress in this damage

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“…It has also been used—with varying effects—in MMA patients with optic atrophy and in Mut −/− mice with renal failure (TT#13). Other explored anti‐oxidants are CB agonist WIN and S‐allylcysteine, glutathione, GM1 ganglioside, melatonin, mitoQ and resveratrol, tiron and trolox, in most cases resulting in a partial or complete reduction of the induced phenotype (TT#15). Methylene blue, an electron transfer mediator, is successfully used in methylmalonic acid‐induced seizures …”

Section: Therapy Targets and Treatment Strategiesmentioning

confidence: 99%

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

Haijes

Hasselt

Jans

et al. 2019

J of Inher Metab Disea

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Despite realizing increased survival rates for propionic acidemia (PA) and methylmalonic acidemia (MMA) patients, the current therapeutic regimen is inadequate for preventing or treating the devastating complications that still can occur. The elucidation of pathophysiology of these complications allows us to evaluate and rethink treatment strategies. In this review we display and discuss potential therapy targets and we give a systematic overview on current, experimental and unexplored treatment strategies in order to provide insight in what we have to offer PA and MMA patients, now and in the future. Evidence on the effectiveness of treatment strategies is often scarce, since none were tested in randomized clinical trials. This raises concerns, since even the current consensus on best practice treatment for PA and MMA is not without controversy. To attain substantial improvements in overall outcome, gene, mRNA or enzyme replacement therapy is most promising since permanent reduction of toxic metabolites allows for a less strict therapeutic regime. Hereby, both mitochondrial‐associated and therapy induced complications can theoretically be prevented. However, the road from bench to bedside is long, as it is challenging to design a drug that is delivered to the mitochondria of all tissues that require enzymatic activity, including the brain, without inducing any off‐target effects. To improve survival rate and quality of life of PA and MMA patients, there is a need for systematic (re‐)evaluation of accepted and potential treatment strategies, so that we can better determine who will benefit when and how from which treatment strategy.

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Treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia

Cited by 31 publications

References 44 publications

Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

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