Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • SwePub (National Library of Sweden)  (16)
Type of Medium
Language
Year
  • 1
    Language: English
    In: Journal of the American College of Cardiology, 09 October 2018, Vol.72(15), pp.1881-1881
    Keywords: Medicine
    ISSN: 0735-1097
    E-ISSN: 1558-3597
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Heart, 3 April 2017, Vol.103(Suppl 1), p.A24
    Description: Cardiac involvement is the main driver of outcome in systemic amyloidosis, but the relationship between amyloid deposits and cellular injury is not well understood. The simple explanation of physical, mechanical replacement of parenchymal tissue seems insufficient, and preliminary studies support the hypothesis that myocardial hypoperfusion could contribute to cell damage in amyloidosis. The aim of this study was: 1) To assess feasibility of fully automated pixel-wise rest myocardial blood flow (MBF) mapping in cardiac amyloidosis during routine clinical scans; 2) To assess the prevalence of myocardial hypoperfusion and correlation with amyloid deposits and disease severity.
    Keywords: Heart ; Deposits ; Perfusion ; Injuries ; Troponin T ; Gadolinium ; Imaging ; Biomarkers ; Amyloidosis ; Inversion ; Mapping ; Beta -Amyloid ; Amyloid ; Imaging;
    ISSN: 1355-6037
    ISSN: 13556037
    E-ISSN: 1468-201X
    E-ISSN: 1468201X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: The New England Journal of Medicine, 2018, Vol.379(1), pp.11-21
    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. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .) Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering RNA targeting transthyretin messenger RNA, to treat the disease.
    Keywords: Administration, Intravenous–Blood ; Adult–Complications ; Aged–Therapy ; Aged, 80 and Over–Chemically Induced ; Amyloid Neuropathies, Familial–Etiology ; Disease Progression–Adverse Effects ; Double-Blind Method–Etiology ; Edema–Therapy ; Female–Analysis ; Gait Disorders, Neurologic–Genetics ; Humans–Adverse Effects ; Infusions, Intravenous–Therapeutic Use ; Least-Squares Analysis–Therapeutic Use ; Male–Therapeutic Use ; Middle Aged–Therapeutic Use ; Polyneuropathies–Therapeutic Use ; Prealbumin–Therapeutic Use ; Quality of Life–Therapeutic Use ; RNA, Small Interfering–Therapeutic Use ; Rnai Therapeutics–Therapeutic Use ; Severity of Illness Index–Therapeutic Use ; Walk Test–Therapeutic Use ; Abridged ; Prealbumin ; RNA, Small Interfering ; Patisiran;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    In: Human Mutation, September 2014, Vol.35(9), pp.E2403-E2412
    Description: Hereditary systemic amyloidosis comprises a group of rare monogenic diseases inherited in an autosomal dominant fashion. It is associated with mutations in genes encoding eight different proteins, including transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A α‐chain, cystatin C, gelsolin and beta‐2‐microglobulin. With support from the EU FP6 EURAMY project we have designed an online registry of genes and mutations in hereditary amyloidosis including their associated clinical phenotypes, with a view to having a single free online portal for the collection and distribution of this information. Users can search the registry by either mutation, phenotype or authors who have published or submitted mutations. It provides a submission form for reporting newly identified mutations. We also wanted to introduce nomenclature which complies with recommendations set out by Human Genome Variation Society and HUGO Gene Nomenclature Committee for description of new and known genetic variants. We hope this registry would be a useful and convenient tool for the medical and scientific community. ©2014 Wiley‐Liss, Inc.
    Keywords: Hereditary Amyloidosis ; Online Registry ; Amyloidogenic And Non‐Amyloidogenic Mutations
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Primary Immunodeficiency Diseases, pp.393-435
    Keywords: Pediatrik ; Pediatrics
    ISBN: 978-3-662-52909-6
    Source: SwePub (National Library of Sweden)
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: European Journal of Nuclear Medicine, 1998, Vol.25(7), pp.709-713
    Description: Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1–5 years beforehand. There was abnormal uptake of 123 I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1–5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123 I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome.
    Keywords: Key words: Amyloidosis ; Polyneuropathy ; Serum amyloid P component ; Scintigraphy ; Liver transplantation
    ISSN: 0340-6997
    E-ISSN: 1619-7089
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Language: English
    In: Journal of Cardiac Failure, August 2019, Vol.25(8), pp.S9-S10
    Description: Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, fatal disease caused by amyloid accumulation in tissues and organs. Historically, patients were grouped by their predominant phenotype: cardiomyopathy or polyneuropathy. However, recent studies have shown that the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy. This analysis describes the prevalence of polyneuropathy signs and symptoms among patients with hATTR amyloidosis with confirmed cardiomyopathy. Patients enrolled in the Phase 3 ENDEAVOUR study had hATTR amyloidosis with cardiomyopathy (n=206) with a documented TTR mutation, amyloid deposition by biopsy or technetium (.sup.99mTc) scintigraphy, echocardiographic evidence of cardiac amyloid involvement, and medical history or clinical evidence of heart failure. Baseline disease characteristics and medical history were analyzed in the overall group and by genotype to identify the presence of polyneuropathy signs and symptoms. The 3 most common genotypes in the Phase 3 study included Val122Ile (n=118), Thr60Ala (n=35), and Val30Met (n=9). Baseline demographics, disease characteristics, and medical history terms are presented in Table 1. Majority of patients had symptomatic heart failure at baseline (61% NYHA Class II and 31% Class III) and medical history of heart failure (85%). By Polyneuropathy Disability (PND) Score at enrollment, symptoms of polyneuropathy were present in the majority of patients; 53% of patients had sensory abnormalities (PND I) or sensorimotor impairment affecting ambulation (PND II). Based on medical history, 54% of patients had a diagnosis that coded to the nervous system disorders based on peripheral neuropathy standard MedDRA query (49% of Val122Ile patients, 66% Thr60Ala patients, and 78% Val30Met patients). hATTR amyloidosis is a debilitating disease with variable genotype-phenotype relationship. In patients with hATTR amyloidosis with cardiomyopathy, signs and symptoms of polyneuropathy were common. The mixed presentation of hATTR amyloidosis highlights the importance of multisystem disease assessment in this patient population. Author Affiliation: (1) Mayo Clinic, Rochester, MN (2) National Amyloidosis Centre, London, United Kingdom (3) Heidelberg University Hospital, Heidelberg, Germany (4) Boston University, Boston, MA (5) Umea University, Umea, Sweden (6) Alnylam Pharmaceuticals, Cambridge, MA (7) Medical University of South Carolina, Charleston, SC Byline: Martha Grogan (1), Philip N. Hawkins (2), Arnt V. Kristen (3), John L. Berk (4), Ole B. Suhr (5), Hollis Lin (6), Madeline Merkel (6), Anastasia McManus (6), Christine Powell (6), John Vest (6), Verena Karsten (6), Daniel P. Judge (7)
    Keywords: Medicine
    ISSN: 1071-9164
    E-ISSN: 1532-8414
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: Annals of Medicine, 17 November 2015, Vol.47(8), pp.625-638
    Description: Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms...
    Keywords: Amyloidosis ; Cardiomyopathies ; Polyneuropathies ; RNA Interference ; Therapeutics ; Transthyretin ; Medicine
    ISSN: 0785-3890
    E-ISSN: 1365-2060
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Nature, 10 August 2011, Vol.476(7359), pp.214-9
    Description: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
    Keywords: Genetic Predisposition to Disease -- Genetics ; Immunity, Cellular -- Immunology ; Multiple Sclerosis -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages