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  • 1
    Language: English
    In: The New England journal of medicine, 22 November 2018, Vol.379(21), pp.2086
    Description: To the Editor: In his editorial describing the NEURO-TTR trial by Benson et al.1 and the related APOLLO trial by Adams et al.,2 Buxbaum3 (July 5 issue) provides a historical and biologic perspective on antisense (inotersen) and RNA interference (patisiran) therapies targeting the gene encoding transthyretin (TTR). He also writes that a post hoc test showed a correlation between a change in serum levels of transthyretin and the modified Neuropathy Impairment Score+7 (mNIS+7) only in patients who received patisiran and not in patients who received inotersen. This analysis included data from both the patients who received placebo and those who . . .
    Keywords: Amyloid Neuropathies, Familial ; Amyloidosis
    ISSN: 00284793
    E-ISSN: 1533-4406
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  • 2
    In: The New England Journal of Medicine, 2012, Vol.366(24), pp.2276-2283
    Description: We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β 2 -microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β 2 -microglobulin, the affected members of this kindred had normal renal function and normal circulating β 2 -microglobulin values. The Asp76Asn β 2 -microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β 2 -microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β 2 -microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding. A kindred with familial amyloidosis was found to have bowel and autonomic dysfunction and the sicca syndrome from an aspartate-to-asparagine alteration at amino acid 76 of β2-microglobulin. Unexpectedly, this alteration promoted fibrillogenesis and tissue deposition. Summary We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β2-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β2-microglobulin, the affected members of this kindred had normal renal function and normal circulating β2-microglobulin values. The Asp76Asn β2-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β2-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β . . .
    Keywords: Amyloidosis, Familial -- Genetics ; Beta 2-Microglobulin -- Genetics;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 3
    In: The New England Journal of Medicine, 2015, Vol.373(12), pp.1106-1114
    Description: Background The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. Methods We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. Results There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. Conclusions Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243 .) A two-step process, in which circulating levels of amyloid P are reduced and then anti–serum amyloid P antibody is given to activate macrophage clearance mechanisms of tissue deposits, appears to reduce amyloid deposits in liver and some other organs. In systemic amyloidosis, the extracellular deposition of normally soluble plasma proteins as insoluble amyloid fibrils damages the structure and function of tissues and organs. 1 Current treatment consists of support or replacement of failing organs and measures to reduce the abundance of the amyloid fibril precursor protein. 1 , 2 A sufficient reduction of precursor supply arrests the accumulation of amyloid and can reduce morbidity and mortality. However, amyloid regression is very slow and often does not occur at all, in contrast to the usually swift clearance of other extracellular debris and efficient tissue remodeling — for example, after trauma. At least 65% . . .
    Keywords: Medicine;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 4
    Language: English
    In: The New England Journal of Medicine, Sept 17, 2015, Vol.373(12), p.1106(9)
    Description: The article describes the investigation of whether administration of a single dose of fully humanized monoclonal IgG1 anti- serum amyloid P component (SAP) antibody after (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) infusion would be nontoxic in patients with different types of systemic amyloidosis and would produce a clinically relevant reduction in amyloid load. The results revealed that treatment with CPHPC followed by an anti-SAP antibody led to a reduction in amyloid load from the liver and some other tissues.
    Keywords: Amyloidosis -- Care And Treatment ; Monoclonal Antibodies -- Dosage And Administration
    ISSN: 0028-4793
    Source: Cengage Learning, Inc.
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  • 5
    In: The New England Journal of Medicine, 2005, Vol.352(22), pp.2356-2356
    Description: To the Editor: Familial amyloidotic polyneuropathy is a fatal autosomal dominant disease caused by amyloidogenic genetic variants of transthyretin. The liver is the predominant source of circulating transthyretin, and liver transplantation is the only treatment available for the disease. 1 Livers explanted from patients with familial amyloidotic polyneuropathy contain only microscopic amyloid deposits in hilar vessels and nerves and are otherwise uninvolved. Since 1995, more than 300 such livers removed at transplantation have been used sequentially as donor grafts for recipients with liver cancer or end-stage liver disease, in so-called domino liver transplantation. 2 We report here a case of systemic transthyretin . . .
    Keywords: Adult–Etiology ; Amyloid Neuropathies, Familial–Surgery ; Carcinoma, Hepatocellular–Complications ; Hepatitis C–Chemistry ; Humans–Surgery ; Liver–Adverse Effects ; Liver Neoplasms–Analysis ; Liver Transplantation–Analysis ; Male–Analysis ; Middle Aged–Analysis ; Prealbumin–Analysis ; Abridged ; Prealbumin;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 6
    In: The New England Journal of Medicine, 2003, Vol.348(25), pp.2583-2584
    Description: To the Editor: Studies of hereditary inflammatory disorders have identified novel genes and pathways that may be involved in inflammation and apoptosis generally. Mutations in one such gene, variously named NALP3, CIAS1, and PYPAF1, were recently identified as the cause of the Muckle–Wells syndrome and the familial cold autoinflammatory syndrome 1 and have lately also been associated with neonatal-onset multisystem inflammatory disease. 2 Interleukin-1 is a key proinflammatory cytokine that contributes to increased synthesis of serum amyloid A protein by hepatocytes during the acute-phase response. The availability of a recombinant interleukin-1–receptor antagonist for clinical use enabled us to undertake a trial of . . .
    Keywords: Amyloidosis -- Drug Therapy ; Receptors, Interleukin-1 -- Antagonists & Inhibitors ; Sialoglycoproteins -- Therapeutic Use;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 7
    In: The New England Journal of Medicine, 2013, Vol.369(9), pp.819-829
    Description: Background Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. Methods We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. Results Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P〈0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. Conclusions ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077 .) Transthyretin amyloidosis is largely caused by synthesis of mutant transthyretin in the liver and deposition of transthyretin in other organs. A therapeutic approach mediated by RNA interference resulted in reduced transthyretin levels in affected patients and in controls. Transthyretin amyloidosis is a life-threatening disorder caused by the deposition of hepatocyte-derived transthyretin amyloid in various tissues and organs.1,2 Circulating transthyretin is derived from the liver3 and can form amyloid deposits in peripheral nerves and in the gastrointestinal tract, heart, and kidneys. Transthyretin is also synthesized by the retina and choroid plexus,4,5 which can lead to vitreal and leptomeningeal deposits. More than 100 genetic variants of the gene encoding transthyretin (TTR) are associated with autosomal dominant forms of the disease, known as familial amyloidotic polyneuropathy6–8 and familial amyloidotic cardiomyopathy.9–11 The most common mutation associated . . .
    Keywords: Medicine;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 8
    Language: English
    In: The New England journal of medicine, 30 April 2015, Vol.372(18), pp.1769
    Description: To the Editor: In their long-term analysis of black American carriers of the V122I allele in the transthyretin gene (TTR), Quarta et al. (Jan. 1 issue)1 confirm reported carrier frequencies2 but find a low prevalence of echocardiographic features of cardiomyopathy and no significant effect on mortality...
    Keywords: African Americans -- Genetics ; Amyloidosis -- Genetics ; Cardiomyopathy, Restrictive -- Genetics ; Heart Failure -- Genetics ; Prealbumin -- Genetics
    ISSN: 00284793
    E-ISSN: 1533-4406
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  • 9
    In: The New England Journal of Medicine, 1990, Vol.323(8), pp.508-513
    Description: Background. In systemic amyloidosis the distribution and progression of disease have been difficult to monitor, because they can be demonstrated only by biopsy. Serum amyloid P component (SAP) is a normal circulating plasma protein that is deposited on amyloid fibrils because of its specific binding affinity for them. We investigated whether labeled SAP could be used to locate amyloid deposits. Methods. Purified human SAP labeled with iodine-123 was given intravenously to 50 patients with biopsy-proved systemic amyloidosis — 25 with the AL (primary) type and 25 with the AA (secondary) type — and to 26 control patients with disease and 10 healthy subjects. Whole-body images and regional views were obtained after 24 hours and read in a blinded fashion. Results. In the patients with amyloidosis the 123 I-SAP was localized rapidly and specifically in amyloid deposits. The scintigraphic images obtained were characteristic and appeared to identify the extent of amyloid deposition in all 50 patients. There was no uptake of the 123 I-SAP by the control patients and the healthy subjects. In all patients with AA amyloidosis the spleen was affected, whereas the scans showed uptake in the heart, skin, carpal region, and bone marrow only in patients with the AL type. Positive images were seen in six patients in whom biopsies had been negative or unsuccessful; in all six, amyloid was subsequently found on biopsy or at autopsy. Progressive amyloid deposition was observed in 9 of 11 patients studied serially. Conclusions. Scintigraphy after the injection of 123 I-SAP can be used for diagnosing, locating, and monitoring the extent of systemic amyloidosis. (N Engl J Med 1990; 323:508–13.) THERE are two main forms of acquired systemic amyloidosis.1,2 AL amyloidosis, formerly known as primary amyloidosis, occurs in patients with B-cell or plasma-cell dyscrasias, in whom fragments of monoclonal immunoglobulin light chains form amyloid fibrils. AA or reactive systemic (secondary) amyloidosis occurs in patients with chronic inflammatory conditions in whom the fibril protein is derived from the circulating acute-phase lipoprotein known as serum amyloid A. Both are serious and usually fatal conditions in which the accumulation of amyloid fibrils in the tissues destroys normal structure and function.1,2 In addition to the fibrils, all amyloid deposits contain amyloid P component, a . . .
    Keywords: Amyloidosis -- Care And Treatment ; Noninvasive Diagnosis -- Methods ; Radioactive Tracers -- Usage ; Amyloidosis -- Diagnosis;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 10
    Language: English
    In: https://doi.org/10.1056/NEJMoa1716153
    Description: BACKGROUND Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, −4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was −6.0±1.7 versus 28.0±2.6 (difference, −34.0 points; P〈0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was −6.7±1.8 versus 14.4±2.7 (difference, −21.1 points; P〈0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus −0.24±0.04 m per second with placebo (difference, 0.31 m per second; P〈0.001), and the least-squares mean change from baseline in the modified BMI was −3.7±9.6 versus −119.4±14.5 (difference, 115.7; P〈0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.
    Keywords: Amiloïdosi ; Rna ; Assaigs Clínics ; Amyloidosis ; Rna ; Clinical Trials
    ISSN: 0028-4793
    Source: Universitat de Barcelona
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