Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran

Ventura, Paolo; Sardh, Eliane; Longo, Nicola; Balwani, Manisha; Plutzky, Jorge; Gouya, Laurent; Phillips, John D.; Rhyee, Sean H.; Fanelli, Mary-Jean; Sweetser, Marianne T.; Petrides, Petro E.

doi:10.1080/17474124.2022.2110469

Cited by 17 publications

(18 citation statements)

References 69 publications

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“…These are likely to be attributable to an impairment in the trans-sulfuration pathway catalyzed by cystathionine β-synthase. This enzyme uses vitamin B6 as a cofactor [55] and S-adenosylmethionine as an allosteric activator of enzyme activity [54].…”

Section: Patients Suffering Frequent Acute Attacks (≥3 Attacks Per Year)mentioning

confidence: 99%

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

Jericó

Córdoba

Sampedro

et al. 2022

Life

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Rare diseases, especially monogenic diseases, which usually affect a single target protein, have attracted growing interest in drug research by encouraging pharmaceutical companies to design and develop therapeutic products to be tested in the clinical arena. Acute intermittent porphyria (AIP) is one of these rare diseases. AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated. This review reports recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. While further studies are needed to optimize gene therapy vectors or large-scale production of liver-targeted PBGD proteins, effective protection of PBGD mRNA against the acute attacks has already been successfully confirmed in mice and large animals, and mRNA transfer technology is being tested in several clinical trials for metabolic diseases.

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Section: Patients Suffering Frequent Acute Attacks (≥3 Attacks Per Year)mentioning

confidence: 99%

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

Jericó

Córdoba

Sampedro

et al. 2022

Life

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“…Serious adverse effects (SAE) were reported in 39% of the patients and especially elevated blood homocysteine, retinal vein occlusion, injection-site reaction, pancreatitis, worsening of chronic renal failure, pulmonary embolism, right iliac thrombophlebitis, and worsening of liver function [ 6 , 7 ]. Moderate or intermediate hyperhomocysteinemia (HHcyt) has been previously reported in AHP with more marked trend in symptomatic patient or those with high excretion of ALA and PBG [ [8] , [9] , [10] , [11] , [12] ]. Homocysteine is an intermediate of sulfur amino acid metabolism, which is further metabolized via re-methylation or transsulfuration pathways ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…A variety of congenital and acquired conditions lead to HHcyt, including inherited metabolic diseases of Hcyt catabolism, cofactor deficiencies and kidney or liver failure [ 15 ]. In AHP patients, various factors may contribute to HHcyt [ 12 ]. Although vitamins B 9 and B 12 levels are within normal values, vitamin B 6 deficiency has been reported in almost half of AHP patients, probably in relation with poor nutritional status and chronic hyperactivity of ALAS1 which could sequestrate cytosolic pyridoxal-phosphate ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Although vitamins B 9 and B 12 levels are within normal values, vitamin B 6 deficiency has been reported in almost half of AHP patients, probably in relation with poor nutritional status and chronic hyperactivity of ALAS1 which could sequestrate cytosolic pyridoxal-phosphate ( Fig. 2 ) [ 8 , 9 , 12 , 16 , 17 ]. Furthermore, Cystathionine β-synthase (CBS), a pivotal enzyme of the transsulfuration pathway, is dependent on heme and vitamin B 6 as cofactors [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Cystathionine β-synthase (CBS), a pivotal enzyme of the transsulfuration pathway, is dependent on heme and vitamin B 6 as cofactors [ 18 ]. It was argued that reducing CBS activity by depleting intra-hepatic vitamin B 6 or lowering heme availability might contribute to HHcyt in AHP patients [ 12 ]. Recently, several case series reported exacerbation of HHcyt in AHP treated with givosiran [ 10 , 11 , [19] , [20] , [21] ].…”

Section: Introductionmentioning

confidence: 99%

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Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review

Redonnet-Vernhet,

Mercié,

Lebreton

et al. 2024

Molecular Genetics and Metabolism Reports

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Elevated homocysteine is negatively correlated with plasma cystathionine β‐synthase activity in givosiran‐treated patients

Keibler,

Sridharan,

Sweetser

et al. 2024

JIMD Reports

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Givosiran is a subcutaneously administered, liver‐targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine β‐synthase (CBS), which uses homocysteine as a substrate. A liquid chromatography‐tandem mass spectrometry‐based assay was adapted to measure circulating CBS activity. Using plasma collected from the Phase III ENVISION study, CBS activity was measured to directly evaluate whether it is associated with elevated homocysteine levels in givosiran‐treated patients. CBS activity was reduced following givosiran treatment and both homocysteine and methionine levels were inversely correlated with CBS activity. Following administration of a supplement containing vitamin B6, a cofactor for CBS, in four patients during the trial, plasma CBS activity was found to increase, mirroring a corresponding decrease in homocysteine levels. These results support the hypothesis that elevated homocysteine levels following givosiran treatment result from a reduction of CBS activity and that vitamin B6 supplementation lowers homocysteine levels by increasing CBS activity.

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Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran

Cited by 17 publications

References 69 publications

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review

Elevated homocysteine is negatively correlated with plasma cystathionine β‐synthase activity in givosiran‐treated patients

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