Current and future treatment approaches for Barth syndrome

Thompson, Rohan; Jefferies, John L.; Wang, Suya; Pu, William T.; Takemoto, Clifford M.; Hornby, Brittany; Heyman, Andrea; Chin, Michael T.; Vernon, Hilary J.

doi:10.1002/jimd.12453

Cited by 24 publications

(25 citation statements)

References 97 publications

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“…A recent study using knockout-Dsg2 ACM murine hearts showed that improved myocardial fibrosis was observed after the activation of PPARA by either fenofibrate treatment or adeno-associated virus injections of PPARA (92). Nevertheless, several clinical trials have investigated the effects of bezafibrate on mitochondrial disease, neutral lipid storage disease, muscle/mitochondrial FAO disorders, and Barth syndrome (93)(94)(95)(96)(97)(98)(99), which reflect impaired mitochondrial function, lipid accumulation, and heart failure as seen in cardiomyopathies. Therefore, the results obtained from these conducted trials might also shield light on its effect on inherited cardiomyopathies.…”

Section: Fao Alteration In Dcm and Hcmmentioning

confidence: 99%

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Gaar-Humphreys

Brink²,

Wekking³

et al. 2023

Front. Cardiovasc. Med.

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Inherited cardiomyopathies caused by pathological genetic variants include multiple subtypes of heart disease. Advances in next-generation sequencing (NGS) techniques have allowed for the identification of numerous genetic variants as pathological variants. However, the disease penetrance varies among mutated genes. Some can be associated with more than one disease subtype, leading to a complex genotype-phenotype relationship in inherited cardiomyopathies. Previous studies have demonstrated disrupted metabolism in inherited cardiomyopathies and the importance of metabolic adaptations in disease onset and progression. In addition, genotype- and phenotype-specific metabolic alterations, especially in lipid metabolism, have been revealed. In this mini-review, we describe the metabolic changes that are associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which account for the largest proportion of inherited cardiomyopathies. We also summarize the affected expression of genes involved in fatty acid oxidation (FAO) in DCM and HCM, highlighting the potential of PPARA-targeting drugs as FAO modulators in treating patients with inherited cardiomyopathies.

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Section: Fao Alteration In Dcm and Hcmmentioning

confidence: 99%

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Gaar-Humphreys

Brink²,

Wekking³

et al. 2023

Front. Cardiovasc. Med.

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“…Surviving BTHS adults display impaired but stabilized cardiac function [42]. Treatment for BTHS cardiomyopathy includes the use of standard heart failure medications, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-adrenergic blockers, and diuretics [42,131]. In the setting of LVNC and/or arrhythmia, low-dose anticoagulation may be www.videleaf.com considered [42].…”

Section: Translating the Basic Research: Potential Approaches To Trea...mentioning

confidence: 99%

“…Restoring TAZ in BTHS patients is a www.videleaf.com straightforward treatment method. Currently, two approaches aiming to restore TAZ in BTHS are under investigation: gene therapy based on adeno-associated virus (AAV) vectormediated gene delivery [14,139] and enzyme replacement therapy using recombinant human TAZ fused to a cellpenetrating peptide [131]. CRISPR/Cas9 and other gene-editing technology provide a second opportunity for gene therapy to correct inherited genetic mutations causing disease [147].…”

Section: Restoring Taz In Bthsmentioning

confidence: 99%

Barth Syndrome Cardiomyopathy: An Update

Pang¹,

Bao²,

Mitchell-Silbaugh³

et al. 2022

Which Factors Contribute to Innovative Performance? A Case Study Applied to the Food and Beverage Industry

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Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experi-mental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies.

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“…The development of an effective and specific therapy for BTHS patients remains challenging, particularly because of the limited number of diagnosed patients, extraordinary phenotype variability, and unpredictable clinical course. One of the most promising therapeutic approaches includes the CL-targeted tetrapeptide SS-31, which is hypothesized to improve mitochondrial inner membrane stability and bioenergetic functions 36 , 37 .…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice

Russo

Rasmo

Signorile

et al. 2022

Sci Rep

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Barth Syndrome (BTHS), a genetic disease associated with early-onset cardioskeletal myopathy, is caused by loss-of-function mutations of the TAFAZZIN gene, which is responsible for remodeling the mitochondrial phospholipid cardiolipin (CL). Deregulation of CL biosynthesis and maturation in BTHS mitochondria result in a dramatically increased monolysocardiolipin (MLCL)/CL ratio associated with bioenergetic dysfunction. One of the most promising therapeutic approaches for BTHS includes the mitochondria-targeted tetrapeptide SS-31, which interacts with CL. Here, we used TAFAZZIN knockdown (TazKD) mice to investigate for the first time whether in vivo administration of SS-31 could affect phospholipid profiles and mitochondrial dysfunction. The CL fingerprinting of TazKD cardiac mitochondria obtained by MALDI-TOF/MS revealed the typical lipid changes associated with BTHS. TazKD mitochondria showed lower respiratory rates in state 3 and 4 together with a decreased in maximal respiratory rates. Treatment of TazKD mice with SS-31 improved mitochondrial respiratory capacity and promoted supercomplex organization, without affecting the MLCL/CL ratio. We hypothesize that SS-31 exerts its effect by influencing the function of the respiratory chain rather than affecting CL directly. In conclusion, our results indicate that SS-31 have beneficial effects on improving cardiac mitochondrial dysfunction in a BTHS animal model, suggesting the peptide as future pharmacologic agent for therapy.

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Current and future treatment approaches for Barth syndrome

Cited by 24 publications

References 97 publications

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Barth Syndrome Cardiomyopathy: An Update

Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice

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