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Acute intermittent porphyria, givosiran, and homocysteine
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2021-06-18 , DOI: 10.1002/jimd.12411
Antonio Fontanellas 1, 2, 3 , Matías A Ávila 1, 2, 3 , Elena Arranz 4 , Rafael Enríquez de Salamanca 4 , Montserrat Morales-Conejo 4, 5
Affiliation  

Acute intermittent porphyria (AIP) is a rare genetic metabolic disease caused by a specific enzyme dysfunction in the hepatic heme biosynthesis pathway. Besides the obvious clinical relevance of a disease in which patients are at risk of acute life-threatening neurovisceral attacks, the study of this disorder is of particular interest because it can provide straightforward proof-of-concept for new molecular therapies and also reveal unexpected metabolic crosstalks. Two previous studies, one from the group of Dr To-Figueras, already reported high prevalence of elevated plasma total homocysteine (P-tHcy) levels (hyperhomocysteinemia, HHcy) in symptomatic AIP, which was more frequent in those patients receiving heme replacement therapy due to recurrent disease.1, 2 HHcy is not a benign condition, as it has been related with the development of cardiovascular and neurological damage. We read with interest a new study from the same group recently published in this Journal,3 where these observations are substantiated and the potential mechanisms underlying HHcy are further addressed. Moreover, an important message in this work is that administration of the newly introduced AIP treatment, givosiran, a siRNA targeting δ-aminolevulinate synthase-1 (ALAS1), the first enzyme of the heme synthesis pathway, in spite of improving clinical AIP symptoms aggravated the impairment in Hcy metabolism, resulting in HHcy and hypermethioninemia in 82% of patients.

We have also observed moderate increased P-tHcy (>15 μmol/L) in 34 of 91 (37%) AIP symptomatic patients (≥1 acute attack in their clinical course) and higher P-tHcy levels in three out of four patients (75%) receiving givosiran (Supporting Information Figure S1A-D). These four patients were in prophylaxis hemin infusions in the context of unstable porphyria. Givosiran injection was associated with significant decrease in excretion of urinary porphyrin precursors in three out of four patients (Supporting Information Figure S1A-D) with an acceptable safety profile in all of them. Indeed, remission of acute porphyria attacks was observed in all four patients after initiation of the givosiran regime and hemin therapy was discontinued. In one patient (Supporting Information Figure S1A), very high P-tHcy was associated with low serum levels of folic acid on months 2 and 4 post-givosiran treatment (2 and 1.8 ng/mL, respectively) and homozygous pathogenic variant (c.665C>T) in the methylene-tetrahydrofolate reductase (MTHFR) gene, involved in Hcy remethylation to methionine.4 Although folic acid replenishment decreased P-tHcy, its levels remained elevated.

As in Dr To-Figueras' work,3 prophylactic hemin therapy was withdrawn in patients treated with givosiran. It is possible that reduced heme availability could lead to dysfunctional cystathionine-β-synthase (CBS) activity, a heme-sensitive enzyme responsible for Hcy clearance through the transsulfuration pathway.4 Both CBS and cystathionine-gamma-lyase (CGL) are pyridoxal-5-phosphate-dependent enzymes, and vitamin B6 supplementation could improve Hcy metabolism via the transsulfuration pathway. Nevertheless, we believe that other mechanisms might also be involved in the development of HHcy in givosiran-treated AIP patients. Heme depletion also results in oxidative stress and inflammation, conditions that promote the inactivation of methionine-adenosyltransferase I/III (MATI/III), the enzyme responsible for the hepatic conversion of methionine into S-adenosylmethionine (SAM)4 (Supporting Information Figure S1E). MATI/III inactivation might not only explain the hypermethioninemia observed in these patients, but might also contribute in part to reduced CBS activity and HHcy, as SAM is an allosteric activator of this enzyme.4 In conclusion, further understanding of the mechanisms underlying the impairment of methionine and Hcy in AIP patients treated with givosiran may offer opportunities to increase the safety of this innovative therapy.

INFORMED CONSENT

Procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent for blood extraction and expanded analyses was obtained from all patients included in the study. The ethical committee of the institution approved the project (Hospital 12 de Octubre, Madrid, Spain). Confidentiality of the results was guaranteed by the hospital protocols and databases. Proof that informed consent was obtained is available upon request. This article does not contain any studies with animal subjects performed by any of the authors.



中文翻译:

急性间歇性卟啉症、givosiran 和同型半胱氨酸

急性间歇性卟啉症(AIP)是一种罕见的遗传代谢疾病,由肝血红素生物合成途径中的特定酶功能障碍引起。除了患者面临急性威胁生命的神经内脏发作风险的疾病的明显临床相关性外,对这种疾病的研究特别令人感兴趣,因为它可以为新的分子疗法提供直接的概念验证,还可以揭示出乎意料的代谢串扰。之前的两项研究,一项来自 To-Figueras 博士的研究,已经报告了症状性 AIP 中血浆总同型半胱氨酸 (P-tHcy) 水平升高(高同型半胱氨酸血症,HHcy)的高患病率,这在接受血红素替代治疗的患者中更为常见,因为对复发性疾病。1, 2HHcy 不是一种良性疾病,因为它与心血管和神经损伤的发展有关。我们感兴趣地阅读了最近发表在本期刊上的同一小组的一项新研究3,其中这些观察得到了证实,并且 HHcy 的潜在机制得到了进一步的解决。此外,这项工作中的一个重要信息是,尽管改善了临床 AIP 症状,但新引入的 AIP 治疗 givosiran 是一种靶向 δ-氨基乙酰丙酸合酶 1 ( ALAS1 )的 siRNA ,血红素合成途径的第一种酶Hcy代谢受损,导致82%的患者出现HHcy和高甲硫氨酸血症。

我们还观察到 91 名(37%)有 AIP 症状的患者(临床过程中≥1 次急性发作)中的 34 名 P-tHcy(>15 μmol/L)中度升高,四分之三的患者 P-tHcy 水平升高( 75%)接受 givosiran(支持信息图 S1A-D)。这四名患者在不稳定卟啉症的情况下进行预防性血红素输注。Givosiran 注射与四分之三的患者尿卟啉前体排泄显着减少有关(支持信息图 S1A-D),所有患者的安全性均可接受。事实上,在开始 givosiran 治疗和停止血红素治疗后,所有四名患者的急​​性卟啉症发作均得到缓解。在一名患者中(支持信息图 S1A),MTHFR ) 基因,参与 Hcy 再甲基化为蛋氨酸。4虽然叶酸补充降低了 P-tHcy,但其水平仍然升高。

与 To-Figueras 博士的工作一样,接受 givosiran 治疗的患者停用了3种预防性血红素治疗。血红素可用性降低可能会导致胱硫醚-β-合酶 (CBS) 活性功能失调,CBS 是一种血红素敏感酶,负责通过转硫途径清除 Hcy。4CBS 和胱硫醚-γ-裂解酶 (CGL) 都是 5-磷酸吡哆醛依赖性酶,补充维生素 B6 可以通过转硫途径改善 Hcy 代谢。尽管如此,我们认为其他机制也可能参与 givosiran 治疗的 AIP 患者 HHcy 的发展。血红素消耗还会导致氧化应激和炎症,这些情况会促进蛋氨酸-腺苷转移酶 I/III (MATI/III) 失活,该酶负责将蛋氨酸在肝脏中转化为 S-腺苷甲硫氨酸 (SAM) 4(支持信息图 S1E)。MATI/III 失活不仅可以解释在这些患者中观察到的高甲硫氨酸血症,而且还可能部分导致 CBS 活性和 HHcy 降低,因为 SAM 是这种酶的变构激活剂。4总之,进一步了解在接受 givosiran 治疗的 AIP 患者中蛋氨酸和 Hcy 受损的潜在机制可能会为提高这种创新疗法的安全性提供机会。

知情同意

程序符合人体实验负责委员会(机构和国家)的道德标准和 1975 年赫尔辛基宣言,并于 2000 年修订。研究中包括的所有患者都获得了血液提取和扩大分析的知情同意书. 该机构的伦理委员会批准了该项目(Hospital 12 de Octubre,马德里,西班牙)。医院协议和数据库保证了结果的机密性。可根据要求提供获得知情同意的证据。本文不包含任何作者对动物受试者进行的任何研究。

更新日期:2021-07-14
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