Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

Guenzel, Adam J.; Hillestad, Matthew L.; Matern, Dietrich; Barry, Michael A.

doi:10.1089/hum.2014.012

Cited by 14 publications

(20 citation statements)

References 28 publications

(33 reference statements)

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“…The authors assume that gene therapy concurrently directed to hepatocytes and muscle cells would result in even better correction, as all tissues require PCC activity. They suggest that treatment of a wide array of tissues would represent the best option for PA disease correction . In a subsequent study, it was demonstrated that AAV‐mediated expression of Pcca resulted in long‐term phenotypic correction, although transgene expression decreased in the liver and in skeletal muscle.…”

Section: Therapy Targets and Treatment Strategiesmentioning

confidence: 99%

“…It was demonstrated that adenovirus serotype 5 resulted only in a transient effect, whereas systemic administration of AAV serotype 8 resulted in more persistent correction of the biochemical phenotype . Next, the effectiveness of systemic therapy with AAV serotype 1 (muscle tropism), serotype 8 (liver tropism) and serotype rh10 (broad tropism) was studied and revealed that AAV serotype 8 in combination with a transthyretin promotor resulted in the most promising correction of the biochemical phenotype . The authors assume that gene therapy concurrently directed to hepatocytes and muscle cells would result in even better correction, as all tissues require PCC activity.…”

Section: Therapy Targets and Treatment Strategiesmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Therapy Targets and Treatment Strategiesmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…This murine model survives into adulthood, while accurately recapitulating biochemical and clinical biomarkers similar to those in patients with PA. This highly useful model has been used to test Ad5 and different AAV vectors (muscle-biased AAV1, liver-biased AAV8 and broadly tropic AAVrh10) carrying a wild-type copy of the pccA gene to induce phenotypic correction [46,47]. Liver-targeted vectors mediated better correction than muscletargeted ones [47].…”

Section: Gene Therapymentioning

confidence: 99%

“…This highly useful model has been used to test Ad5 and different AAV vectors (muscle-biased AAV1, liver-biased AAV8 and broadly tropic AAVrh10) carrying a wild-type copy of the pccA gene to induce phenotypic correction [46,47]. Liver-targeted vectors mediated better correction than muscletargeted ones [47]. The effect, monitored as decrease in circulating diagnostic metabolites, is long-lasting, with sex-biased loss of expression of the transgene in liver and skeletal muscle, reducing the efficacy in females [48].…”

Section: Gene Therapymentioning

confidence: 99%

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Understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies

Richard

Pérez

Pérez‐Cerdá

et al. 2015

Expert Opinion on Orphan Drugs

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Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Dimitrov

Molema

Williams

et al. 2020

J of Inher Metab Disea

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Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

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Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

Cited by 14 publications

References 28 publications

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

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

Understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

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