Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran

AbstractIn 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that  results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-basedTTR gene silencing. The silencing process  involves the binding of siRNA guide strand to 3′-untranslated region sequence of both mutant and wild-typeTTR messenger RNA, which culminates in theTTR mRNA cleavage by the RNA-induced silencing complex (RISC)  as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs a...
Source: Molecular Diagnosis and Therapy - Category: Molecular Biology Source Type: research

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Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/ Longevity Industry Consulting Services Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out m...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications. To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence? https://www.fightaging.org/archives/2019/11/to-what-degree-does-loss-of-skeletal-muscle-with-age-contribute-to-immunosenescence/ Sarcopenia, the progressive loss of muscle mass and strength, is characteristic of aging. A perhaps surprisingly large fraction of the losses can be averted by strength training, but there are nonetheless inexorable process...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract The misfolding, aggregation and fibrillation of human islet amyloid polypeptide (hIAPP) has been acknowledged as a hallmark event in type-II diabetes. Hence, inhibiting the misfolding, aggregation and fibrillation of hIAPP have been accepted as a vital factor to treat the disease. Here cichoric acid was extracted from witloof to explore its inhibition effects on misfolding, aggregation and fibrillation of hIAPP. Thioflavin-T (ThT) fluorescence assay, dynamic light scattering (DLS) and atomic force microscopy (AFM) images showed that cichoric acid inhibited the aggregation and fibrillation of hIAPP in a do...
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Tags: Int J Biol Macromol Source Type: research
CONCLUSION: We propose that it is now necessary to consider whether neuroinflammation in Alzheimer's disease affects inflammation in the pancreas related to diabetes. PMID: 31692443 [PubMed - as supplied by publisher]
Source: Current Alzheimer Research - Category: Neurology Authors: Tags: Curr Alzheimer Res Source Type: research
Publication date: Available online 23 October 2019Source: Pathology - Research and PracticeAuthor(s): Andrew Lytle, Farbod Darvishian, Ugur OzerdemAbstractAmyloidosis is characterized by extracellular deposition of insoluble protein fibrils in a beta-pleated sheet configuration. Breast amyloidosis is a rare entity which has previously been reported to present with localized involvement, or as a late manifestation of systemic amyloidosis. However, descriptions of the clinicopathologic features of localized breast amyloidosis remain limited. A retrospective search for breast amyloidosis diagnosed at our institution yielded 1...
Source: Pathology Research and Practice - Category: Pathology Source Type: research
wara T, Perczel A Abstract The amyloid formation of the folded segment of a variant of Exenatide (a marketed drug for Type-2 Diabetes Mellitus ) was studied by ECD and NMR. We found that the optimum temperature for E5 protein amyloidosis coincides with body temperature and requires well below physiological salt concentration. Decomposition of the ECD spectra and its barycentric representation on the folded-unfolded-amyloid potential energy surface allowed us to monitor the full range of molecular transformation of amyloidogenesis. We identified points of no return ( e.g. T =37°C, pH =4.1, c E5 =250µM, c ...
Source: Chemistry - Category: Chemistry Authors: Tags: Chemistry Source Type: research
Abstract Amyloidosis is characterized by extracellular deposition of insoluble protein fibrils in a beta-pleated sheet configuration. Breast amyloidosis is a rare entity which has previously been reported to present with localized involvement, or as a late manifestation of systemic amyloidosis. However, descriptions of the clinicopathologic features of localized breast amyloidosis remain limited. A retrospective search for breast amyloidosis diagnosed at our institution yielded 10 cases of breast amyloidosis. All patients were female, with a mean age of 69. Median follow-up for survival or progression was 13 month...
Source: Pathology, Research and Practice - Category: Pathology Authors: Tags: Pathol Res Pract Source Type: research
Publication date: September–October 2019Source: Heart &Lung, Volume 48, Issue 5Author(s): IntroductionHereditary transthyretin (TTR) amyloidosis (hATTR) is a rare, progressive, and fatal disease. The disease is caused by misfolded TTR that builds up as amyloid in major organ systems, especially cardiac tissue and nerves, causing cardiomyopathy (CM) and polyneuropathy (PN), respectively. hATTR causes significant morbidity and a progressive decline in patient quality of life (QOL), severely limiting activities of daily living.PurposeTo evaluate the effect of inotersen, an antisense oligonucleotide inhibitor of TTR ...
Source: Heart and Lung: The Journal of Acute and Critical Care - Category: Respiratory Medicine Source Type: research
Abstract Human islet amyloid polypeptide (hIAPP, amylin) may self-aggregate and rupture the membrane of β cells, which is closely correlated with the pathogenesis of type 2 diabetes mellitus (T2DM). Hence, suppressing amyloidogenic hIAPP may be beneficial for the treatment of diabetes. As an important part of hIAPP, the fragment hIAPP19-37 was studied in this work to explore their disaggregation and cellular behavior regulation by some selected Au complexes, as follows: dichloro diethyl dithiocarbamate Au complex [AuCl2(DDTC)] (1), dichloro pyrrolidine dithiocarbamate Au complex [AuCl2(PDT)] (2), dichloro 4-4...
Source: Journal of Inorganic Biochemistry - Category: Biochemistry Authors: Tags: J Inorg Biochem Source Type: research
ConclusionsEarly detection and treatment of gastrointestinal disturbances is key to the successful treatment of this devastating disease. Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in hereditary transthyretin amyloidosis and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder.
Source: Clinical Autonomic Research - Category: Research Source Type: research
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