Pyrophosphate Treatment in Pseudoxanthoma Elasticum (PXE)-Preventing ReOcclusion After Surgery for Critical Limb Ischaemia

Uusitalo, Hannu; kési, Natália T; Pelttari, Saku; Váradi, András; Nevalainen, Pasi; ki, Suvi V r m

doi:10.31487/j.scr.2019.04.02

Cited by 12 publications

(9 citation statements)

References 5 publications

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“…To reduce the ion load and the amount of sodium in PP i , we first turned to the Na 2 H 2 P 2 O 7 salt form which contains half as much sodium as the previously utilized tetrasodium (Na 4 P 2 O 7 ) variant 22 . A case report has been published describing oral pyrophosphate treatment of a PXE patient utilizing Na 2 H 2 P 2 O 7 dissolved in water 29 . To avoid the unpleasant taste, we used capsulated PP i salts instead of water‐based solution as the form of delivery.…”

Section: Resultsmentioning

confidence: 99%

“…22 A case report has been published describing oral pyrophosphate treatment of a PXE patient utilizing Na 2 H 2 P 2 O 7 dissolved in water. 29 To avoid the unpleasant taste, we used capsulated PP i salts instead of water-based solution as the form of delivery. Two different capsules were tested: gelatin and HPMCP-type cellulose capsules, which can resist dissolution at the acidic pH of gastric fluid.…”

Section: Re Sults and Discussionmentioning

confidence: 99%

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Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum

Kozák

Fülöp

Tõkési

et al. 2021

Experimental Dermatology

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Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibres in the skin, eyes and the cardiovascular system. Skin findings often lead to early diagnosis of PXE, but currently, no specific treatment exists to counteract the progression of symptoms. PXE belongs to a group of Mendelian calcification disorders linked to pyrophosphate metabolism, which also includes generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). Inactivating mutations in ABCC6, ENPP1 and NT5E are the genetic cause of these diseases, respectively, and all of them result in reduced inorganic pyrophosphate (PP i ) concentration in the circulation. Although PP i is a strong inhibitor of ectopic calcification, oral supplementation therapy was initially not considered because of its low bioavailability. Our earlier work however demonstrated that orally administered pyrophosphate inhibits ectopic calcification in the animal models of PXE and GACI, and that orally given Na 4 P 2 O 7 is absorbed in humans. Here, we report that gelatin-encapsulated Na 2 H 2 P 2 O 7 has similar absorption properties in healthy volunteers and people affected by PXE. The sodium-free K 2 H 2 P 2 O 7 form resulted in similar uptake in healthy volunteers and inhibited calcification in Abcc6 −/− mice as effectively as its sodium counterpart. Novel pyrophosphate compounds showing higher bioavailability in mice were also identified.Our results provide an important step towards testing oral PP i in clinical trials in PXE, or potentially any condition accompanied by ectopic calcification including diabetes, chronic kidney disease or ageing.

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Section: Resultsmentioning

confidence: 99%

Section: Re Sults and Discussionmentioning

confidence: 99%

Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum

Kozák

Fülöp

Tõkési

et al. 2021

Experimental Dermatology

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“…We have learned much about ABCC6 [ 21 ] since its initial discovery 20 years ago [ 5 , 6 , 7 ], from its transcriptional regulation [ 215 , 216 , 217 ], expression profile [ 79 , 81 , 128 ], and molecular function and connections to an existing molecular pathway [ 8 , 9 ], to means and ways to rescue this transporter and treatments for PXE [ 18 , 19 , 92 , 98 , 99 ]. In two decades, PXE has gone from gene discovery to early clinical trials [ 126 , 218 ], a remarkable feat for rare disorders with significant morbidity but low mortality. At the time of this writing, PXE alone has been the subject of more than 2000 peer-reviewed publications (PubMed citations) as well as many other book chapters and reviews.…”

Section: Discussionmentioning

confidence: 99%

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

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“…Subsequent studies demonstrated that oral administration of tetrasodium-PPi inhibited connective tissue mineralization in both Abcc6 −/− and Enpp1 asj mice [ 16 ]. Further modifications, including use of a disodium-PPi, was tested in individuals with PXE, without apparent gastrointestinal side effects, potentially providing a new treatment modality for PXE and related ectopic mineralization disorders [ 71 ]. Based on these studies, a disodium-PPi absorption trial in PXE patients is under way (NCT04441671; last updated 22 June 2020).…”

Section: Therapy Development For Ectopic Mineralization Disordersmentioning

confidence: 99%

Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

Luo

Cao

et al. 2020

JCM

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Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point.

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Pyrophosphate Treatment in Pseudoxanthoma Elasticum (PXE)-Preventing ReOcclusion After Surgery for Critical Limb Ischaemia

Cited by 12 publications

References 5 publications

Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum

Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

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