Hyperhomocysteinemia in patients with acute porphyrias: a possible effect of ALAS1 modulation by siRNAm therapy and its control by vitamin supplementation

Ricci, Andrea; Marcacci, M; Cuoghi, Chiara; Pietrangelo, Antonello; Ventura, Paolo

doi:10.1016/j.ejim.2021.06.023

Cited by 17 publications

(23 citation statements)

References 9 publications

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“…As 2 SAEs of blood homocysteine increases were observed in the present ENVISION study, 36 analyses of blood homocysteine levels were performed on exploratory samples, which included levels collected before, during, and after givosiran treatment. During these analyses, blood homocysteine levels were also noted to be increased compared with available baseline levels 50,51 . Blood homocysteine levels increased in all patients in one analysis (9/9 patients) and in most patients in the second analysis (14/15 patients) 50,51 .…”

Section: Discussionmentioning

confidence: 89%

Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study

Ventura

Bonkovsky

Gouya

et al. 2021

Liver International

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Background & Aims Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria. Methods Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. Results Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period. Conclusions Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

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Section: Discussionmentioning

confidence: 89%

Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study

Ventura

Bonkovsky

Gouya

et al. 2021

Liver International

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“…Givosiran is a small interfering RNA (siRNA) that targets ALAS mRNA in hepatocytes, exploiting the RNA-induced silencing complex (RISC) to impair its translation. Even though some adverse events, possibly related to induction of relative heme deficiency [144][145][146] and partly reversible [144,147], have been recorded, givosiran has proved to be very effective in reducing the biochemical ALAS is induced by porphyrinogenic stimuli (e.g., fasting, alcohol, or certain drugs) which supposedly induce an increased metabolic demand for heme. In particular, fasting induces ALAS1 expression via the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α).…”

Section: Discussionmentioning

confidence: 99%

“…Givosiran is a small interfering RNA (siRNA) that targets ALAS mRNA in hepatocytes, exploiting the RNA-induced silencing complex (RISC) to impair its translation. Even though some adverse events, possibly related to induction of relative heme deficiency [ 144 , 145 , 146 ] and partly reversible [ 144 , 147 ], have been recorded, givosiran has proved to be very effective in reducing the biochemical markers of disease, lowering the mean annualized rate of porphyric attacks, and improving the quality of life of patients [ 143 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

et al. 2021

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Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.

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“…It is hypothesized that heme depletion could interfere with cystathionine-beta-synthase, which is the enzyme primarily responsible for the conversion of homocysteine, although alternative mechanisms could also be involved. Supplementation with pyridoxal phosphate (vitamin B6) led to improved or normalized homocysteine levels in some cases [48][49][50][51].…”

Section: Contemporary Approaches To Managementmentioning

confidence: 99%

Porphyrias in the Age of Targeted Therapies

Erwin

Balwani

2021

Diagnostics

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The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations.

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Hyperhomocysteinemia in patients with acute porphyrias: a possible effect of ALAS1 modulation by siRNAm therapy and its control by vitamin supplementation

Cited by 17 publications

References 9 publications

Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study

Efficacy and safety of givosiran for acute hepatic porphyria: 24‐month interim analysis of the randomized phase 3 ENVISION study

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

Porphyrias in the Age of Targeted Therapies

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