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The New England Journal of Medicine Jun 2020Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.
METHODS
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.
RESULTS
A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.
CONCLUSIONS
Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).
Topics: Acetylgalactosamine; Adult; Aminolevulinic Acid; Double-Blind Method; Fatigue; Female; Humans; Injections, Subcutaneous; Least-Squares Analysis; Liver; Male; Nausea; Pain; Patient Outcome Assessment; Porphobilinogen; Porphyria, Acute Intermittent; Pyrrolidines; RNAi Therapeutics; Renal Insufficiency, Chronic; Transaminases
PubMed: 32521132
DOI: 10.1056/NEJMoa1913147 -
Human Mutation Nov 2021Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the... (Review)
Review
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. We collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States. All data were analyzed to determine common alleles, geographic distribution, level of homozygosity, and genotype-phenotype correlation. Moreover, variants were classified according to their pathogenicity as suggested by ACMG. Including those previously published, we assembled 446 unique variants, among which 68 were novel, from 1190 subjects (including newborn screening positive subjects). Variants' distribution was missense (65.0%), followed by nonsense (8.1%), splicing (7.2%), small frameshift deletions(del)/insertions(ins) (7.0%), intronic (4.0%), and large del/ins and complex rearrangements (3.8%). Half (50.4%) of the subjects were homozygous, 37.1% were compound heterozygous, and 10.7% had only one variant detected. The novel variants underwent in silico analysis to evaluate their pathogenicity. All variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) to make them publicly available. Mutation updates are essential for the correct molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease management.
Topics: Chondroitinsulfatases; Genetic Association Studies; Humans; Mucopolysaccharidosis IV; Mutation
PubMed: 34387910
DOI: 10.1002/humu.24270 -
Clinical Pharmacology and Therapeutics Feb 2021Vutrisiran (ALN-TTRsc02) is a liver-directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)-mediated amyloidosis.... (Randomized Controlled Trial)
Randomized Controlled Trial
Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine-Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects.
Vutrisiran (ALN-TTRsc02) is a liver-directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)-mediated amyloidosis. This phase I, randomized, single-blind, placebo-controlled, single ascending dose study evaluated the pharmacodynamics, pharmacokinetics, and safety profile of subcutaneously administered vutrisiran (5-300 mg) in healthy subjects (n = 80). Vutrisiran treatment achieved potent and sustained TTR reduction in a dose-dependent manner, with mean maximum TTR reduction of 57-97%, maintained for ≥ 90 days post dose. Vutrisiran was rapidly absorbed (peak plasma concentration 3-5 hours post dose), had a short plasma half-life (4.2-7.5 hours), and plasma concentrations increased in a dose-proportional manner. Pharmacodynamic and pharmacokinetic results were similar in Japanese and non-Japanese subjects. Vutrisiran had an acceptable safety profile; the most common treatment-related adverse event was mild, transient injection site reactions in four (6.7%) vutrisiran-treated subjects. The favorable pharmacokinetic, pharmacodynamic, and safety results observed here support vutrisiran's continued clinical development.
Topics: Acetylgalactosamine; Adult; Amyloid Neuropathies, Familial; Asian People; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Healthy Volunteers; Humans; Male; Prealbumin; RNA; Single-Blind Method
PubMed: 32599652
DOI: 10.1002/cpt.1974 -
Nature Biomedical Engineering Oct 2019Homeostatic antigen presentation by hepatic antigen-presenting cells, which results in tolerogenic T-cell education, could be exploited to induce antigen-specific...
Homeostatic antigen presentation by hepatic antigen-presenting cells, which results in tolerogenic T-cell education, could be exploited to induce antigen-specific immunological tolerance. Here we show that antigens modified with polymeric forms of either N-acetylgalactosamine or N-acetylglucosamine target hepatic antigen-presenting cells, increase their antigen presentation and induce antigen-specific tolerance, as indicated by CD4 and CD8 T-cell deletion and anergy. These synthetically glycosylated antigens also expanded functional regulatory T cells, which are necessary for the durable suppression of antigen-specific immune responses. In an adoptive-transfer mouse model of type-1 diabetes, treatment with the glycosylated autoantigens prevented T-cell-mediated diabetes, expanded antigen-specific regulatory T cells and resulted in lasting tolerance to a subsequent challenge with activated diabetogenic T cells. Glycosylated autoantigens targeted to hepatic antigen-presenting cells might enable therapies that promote immune tolerance in patients with autoimmune diseases.
Topics: Acetylgalactosamine; Acetylglucosamine; Adoptive Transfer; Animals; Antigen Presentation; Autoantigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Immune Tolerance; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Spleen; T-Lymphocytes
PubMed: 31358881
DOI: 10.1038/s41551-019-0424-1 -
Nature Jun 2022The composition of the intestinal microbiome varies considerably between individuals and is correlated with health. Understanding the extent to which, and how, host...
The composition of the intestinal microbiome varies considerably between individuals and is correlated with health. Understanding the extent to which, and how, host genetics contributes to this variation is essential yet has proved to be difficult, as few associations have been replicated, particularly in humans. Here we study the effect of host genotype on the composition of the intestinal microbiota in a large mosaic pig population. We show that, under conditions of exacerbated genetic diversity and environmental uniformity, microbiota composition and the abundance of specific taxa are heritable. We map a quantitative trait locus affecting the abundance of Erysipelotrichaceae species and show that it is caused by a 2.3 kb deletion in the gene encoding N-acetyl-galactosaminyl-transferase that underpins the ABO blood group in humans. We show that this deletion is a ≥3.5-million-year-old trans-species polymorphism under balancing selection. We demonstrate that it decreases the concentrations of N-acetyl-galactosamine in the gut, and thereby reduces the abundance of Erysipelotrichaceae that can import and catabolize N-acetyl-galactosamine. Our results provide very strong evidence for an effect of the host genotype on the abundance of specific bacteria in the intestine combined with insights into the molecular mechanisms that underpin this association. Our data pave the way towards identifying the same effect in rural human populations.
Topics: ABO Blood-Group System; Acetylgalactosamine; Animals; Bacteria; Gastrointestinal Microbiome; Genotype; N-Acetylgalactosaminyltransferases; Quantitative Trait Loci; Swine
PubMed: 35477154
DOI: 10.1038/s41586-022-04769-z -
Nephrologie & Therapeutique Dec 2022Small interfering RNA (siRNAs) are double-stranded RNAs of around 20 base pairs in length that trigger RNAi machinery, which promotes degradation of a target mRNA...
Small interfering RNA (siRNAs) are double-stranded RNAs of around 20 base pairs in length that trigger RNAi machinery, which promotes degradation of a target mRNA avoiding protein translation. SiRNAs are liver-targeted, using tris N-acetylgalactosamine (GalNAc) as the targeting ligand. This discovery received the Nobel Prize for medicine and physiology in 2006 and lead to substantial therapeutic advances. Application field and development of these siRNA has been very fast. Indeed, patisiran has been released in 2018 for hereditary transthyretin amyloidosis. This first treatment showed the security and efficacy of such a product. Since, treatments have been developed for acute hepatic porphyria and primary hyperoxaluria. The current pipeline for new siRNA development is ambitious; clinical trial are ongoing in nephrology, as in the IgA nephropathy. Frequent diseases are also targeted such as hypertension or hypercholesterolemia. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.
Topics: Humans; Nephrologists; RNA, Small Interfering; Amyloid Neuropathies, Familial; Hypertension; Porphyrias, Hepatic
PubMed: 36585119
DOI: 10.1016/S1769-7255(22)00646-0 -
Drugs Feb 2020Givosiran (Givlaari™) is an aminolevulinate synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to a ligand to enable specific delivery of the... (Review)
Review
Givosiran (Givlaari™) is an aminolevulinate synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to a ligand to enable specific delivery of the siRNA to hepatocytes. This results in downregulation of ALAS1 mRNA and prevents accumulation of neurotoxic δ-aminolevulinic acid and porphobilinogen levels that are associated with acute porphyria attacks. Givosiran is being developed by Alnylam Pharmaceuticals for the treatment of acute hepatic porphyria (AHP). In November 2019, givosiran was approved in the USA for the treatment of adults with AHP based on the positive results from the multinational, phase III ENVISION trial. In the EU, givosiran received a positive opinion in January 2020 for the treatment of AHP in adults and adolescents aged 12 years and older. This article summarizes the milestones in the development of givosiran leading to this first approval for the treatment of adults with AHP.
Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Drug Approval; Enzyme Inhibitors; Humans; Porphobilinogen Synthase; Porphyrias, Hepatic; Pyrrolidines; RNA, Messenger
PubMed: 32034693
DOI: 10.1007/s40265-020-01269-0 -
Nature Jan 2024Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established, little is known about how host genetics regulates... (Meta-Analysis)
Meta-Analysis
Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.
Topics: Humans; Acetylgalactosamine; Bacteria; Cohort Studies; Computer Simulation; Faecalibacterium prausnitzii; Gastrointestinal Microbiome; Genome, Human; Genotype; Host Microbial Interactions; In Vitro Techniques; Metagenome; Multigene Family; Netherlands; Tanzania
PubMed: 38172637
DOI: 10.1038/s41586-023-06893-w -
Nature Oct 2021Humans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a barrier that separates...
Humans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a barrier that separates these microorganisms from the intestinal epithelium. Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate degradation of the complex O-glycans found in mucins. In the distal colon, these glycans are heavily sulfated, but specific sulfatases that are active on colonic mucins have not been identified. Here we show that sulfatases are essential to the utilization of distal colonic mucin O-glycans by the human gut symbiont Bacteroides thetaiotaomicron. We characterized the activity of 12 different sulfatases produced by this species, showing that they are collectively active on all known sulfate linkages in O-glycans. Crystal structures of three enzymes provide mechanistic insight into the molecular basis of substrate specificity. Unexpectedly, we found that a single sulfatase is essential for utilization of sulfated O-glycans in vitro and also has a major role in vivo. Our results provide insight into the mechanisms of mucin degradation by a prominent group of gut bacteria, an important process for both normal microbial gut colonization and diseases such as inflammatory bowel disease.
Topics: Acetylgalactosamine; Animals; Bacteroides; Colon; Crystallography, X-Ray; Female; Galactose; Gastrointestinal Microbiome; Humans; Male; Mice; Models, Molecular; Mucins; Substrate Specificity; Sulfatases
PubMed: 34616040
DOI: 10.1038/s41586-021-03967-5 -
Frontiers in Pharmacology 2022RNA interference has become increasingly used for genetic therapy following the rapid development of oligonucleotide drugs. Significant progress has been made in its... (Review)
Review
RNA interference has become increasingly used for genetic therapy following the rapid development of oligonucleotide drugs. Significant progress has been made in its delivery system and implementation in the treatment of target organs. After a brief introduction of RNA interference technology and siRNA, the efficiency and stability of GalNAc-siRNA conjugates are highlighted since several oligonucleotide drugs of GalNAc have been approved for clinical use in recent years. The structure and features of GalNAc-siRNA conjugates are studied and the clinical efficiency and limitations of oligonucleotide-based drugs are summarized and investigated. Furthermore, another delivery system, lipid nanoparticles, that confer many advantages, is concluded, includ-ing stability and mass production, compared with GalNAc-siRNA conjugates. Importantly, developing new approaches for the use of oligonucleotide drugs brings hope to genetic therapy.
PubMed: 36588695
DOI: 10.3389/fphar.2022.1090237