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48-506: The company is a spin-off from the Max Planck Institute for Biophysical Chemistry . In 2002, Alnylam was founded by scientists Phillip Sharp , Paul Schimmel , David Bartel , Thomas Tuschl , and Phillip Zamore , and by investors Christoph Westphal and John Kennedy Clarke; John Maraganore was the founding CEO. The company was named after Alnilam , a star in Orion 's belt. The spelling

96-577: A polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Amyloid-beta precursor protein is an ancient and highly conserved protein . In humans , the gene APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases . Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 639 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in

144-567: A single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation. The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity. As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize

192-516: A 12 percent stake in Alnylam and increased its rights to several of the company's drugs for $ 700 million. In a separate transaction Alnylam announced that it had purchased Merck & Co. 's Sirna Therapeutics , for $ 25 million cash and $ 150 million in stock. In 2015, the company had $ 41 million in revenue and a market cap of $ 5.2 billion. In 2016, the company purchased land in Norton, Massachusetts to build

240-594: A 40% reduction in the formation of amyloid beta in vitro. A number of different structural domains that fold mostly on their own have been found in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper -binding domain (CuBD) interacting tightly together. A serine protease inhibitor domain, absent from

288-450: A decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia. In neurons of the human brain , somatic recombination occurs frequently in the gene that encodes APP. Neurons from individuals with sporadic Alzheimer's disease show greater APP gene diversity due to somatic recombination than neurons from healthy individuals. Molecules synthesized in

336-604: A license and collaboration agreement with Alnylam Pharmaceuticals. Alnylam still does not earn money, but writes losses. The losses ("GAAP Operating Loss") from Alnylam were around $ 650 million in the late 2020. Alnylam expects to achieve net profits financially in 2022 or 2023. In July 2023, Roche partnered with Alnylam Pharmaceuticals in a deal worth $ 2.8 billion for the development of a hypertension drug. In 2016, Alnylam Pharmaceuticals had 18 potential treatments in various development stages in genetic medicine, cardiometabolic disease and hepatic infectious disease. In late 2016,

384-501: A likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease. Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. Experimental models of Alzheimer's disease are commonly used by researchers to gain better understandings about the biological function of APP in disease pathology and progression. The most-substantiated role for APP

432-512: A major genetic risk factor for Alzheimer's. The amyloidogenic processing of APP has been linked to its presence in lipid rafts . When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. Gamma secretase activity has also been associated with lipid rafts. The role of cholesterol in lipid raft maintenance has been cited as

480-456: A manufacturing facility. In October 2016 the Phase III clinical trial of the company's lead product, revusiran, was halted due to increased deaths in the drug arm of the trial, and the company said it was terminating development of the compound. On October 10, 2018, Alnylam appoints Margaret Hamburg to Board of Directors. Prior to this, from May 2009 to April 2015, she serves as Commissioner of

528-496: A nonexclusive alliance with Hoffmann-La Roche , in which Alnylam received $ 331 million in exchange for access to its technology platform. and also partnered with Ionis Pharmaceuticals to found the company Regulus Therapeutics , focused on microRNA therapeutics. In 2009, the company formed alliances with Cubist Pharmaceuticals and Kyowa Hakko Kirin to market a drug targeted at respiratory syncytial virus . In 2010, it expanded its previous collaboration with Medtronic to include

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576-411: A rapid acquisition technique for magnetic resonance imaging termed FLASH MRI (fast low angle shot) technique which allowed for a 100-fold reduction of the measuring times of cross-sectional and three-dimensional images. The FLASH technique led the ground for many modern MRI applications in diagnostic imaging. In 2000, two International Max Planck Research Schools (IMPRS) were established together with

624-522: A treatment for transthyretin-mediated amyloidosis, a hereditary disease in Asia. In February 2013, it formed a partnership with The Medicines Company to develop a drug to treat a genetic form of high cholesterol. In July 2013, during a Phase I trial Alnylam demonstrated statistically significant reduction of a protein called transthyretin, or TTR and demonstrated human efficacy with intravenous and subcutaneous modes of administration. In 2014, Sanofi Genzyme acquired

672-457: Is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons . It functions as a cell surface receptor and has been implicated as a regulator of synapse formation , neural plasticity , antimicrobial activity, and iron export . It is coded for by the gene APP and regulated by substrate presentation . APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ),

720-464: Is cellular logistics controlled? On the organismal level, researchers at the institute study the circadian rhythms of the vertebrate, or differentiation and development in multicellular organisms. To obtain even deeper insights into the nanocosmos of living cells, the institute employs ultra-high resolution microscopy, nuclear magnetic resonance spectroscopy and tomography, mass spectrometry , optical spectroscopy , or atomistic computer simulations. At

768-635: Is in synaptic formation and repair; its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling , long-term potentiation , and cell adhesion have been proposed and supported by as-yet limited research. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch . APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. On

816-541: Is indicated in the United States as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. The effect of Leqvio on cardiovascular morbidity and mortality is being explored in clinical trials currently underway. Novartis obtained global rights to develop, manufacture and commercialize Leqvio under

864-429: Is predominantly expressed in neuronal cells and is crucial for normal neuronal function. APP751 and APP770 are more widely expressed in non-neuronal tissues but exhibit distinct expression patterns during neuron differentiation. The differential expression of these isoforms plays a significant role in cellular processes such as neurodevelopment, synaptic plasticity, and the pathogenesis of Alzheimer's disease. Understanding

912-694: Is seeking the committee's input on the clinical meaningfulness and patient populations for patisiran use potentially challenging Pfizer's tafamidis dominance in ATTR-CM treatment. A decision on Alnylam's application is expected by October 8, 2023. Patisiran was previously approved in 2018 for hereditary ATTR amyloidosis polyneuropathy, becoming the first RNA interference therapeutic approved by the FDA. Max Planck Institute for Biophysical Chemistry The Max Planck Institute for Biophysical Chemistry ( German : Max-Planck-Institut für biophysikalische Chemie ), also known as

960-665: The Karl-Friedrich Bonhoeffer Institute ( German : Karl-Friedrich-Bonhoeffer-Institut ), was a research institute of the Max Planck Society , located in Göttingen , Germany. On January 1, 2022, the institute merged with the Max Planck Institute for Experimental Medicine in Göttingen to form the Max Planck Institute for Multidisciplinary Sciences . This was the only Max Planck Institute (MPI) that combined

1008-470: The CHDI Foundation in its Huntington's disease focused research. In 2011, it partnered with GlaxoSmithKline to develop RNAi technology enhancing vaccine production. The company entered into a 10-year alliance with Monsanto in 2012, to develop biotech solutions for the farming industry by developing natural molecules for crop protection. In 2012, it formed a partnership with Sanofi Genzyme to develop

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1056-648: The Medicines and Healthcare Products Regulatory Agency in the United Kingdom to initiate a Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) for the treatment of Alzheimer's disease and cerebral amyloid angiopathy . On December 22, 2021, Novartis announced that the US Food and Drug Administration (FDA) approved Leqvio (inclisiran), a small interfering RNA (siRNA) therapy to lower low-density lipoprotein cholesterol. Leqvio

1104-490: The FDA raised doubts about the efficacy of patisiran for treating cardiomyopathy associated with transthyretin -mediated amyloidosis (ATTR-CM). The FDA's Cardiovascular and Renal Drugs Advisory Committee meeting is scheduled for September 13, 2023. Although the APOLLO-B study met key endpoints, the FDA questioned the clinical significance of the results particularly for patients not on background therapy with tafamidis . The FDA

1152-783: The Georg August University Göttingen, the German Primate Center and the Max Planck Institute for Experimental Medicine: the IMPRS for Molecular Biology and the IMPRS for Neurosciences (in cooperation with the Max Planck Institute for Dynamics and Self-Organization and the European Neuroscience Institute Göttingen). A third graduate school, the IMPRS for Physics of Biological and Complex Systems,

1200-637: The Kaiser Wilhelm Institute, became the founding director of the new institute. He was one of the first researchers who applied physical-chemical methods in biological research and thus combined different disciplines of natural sciences in research. In 1971, the MPI for Physical Chemistry merged with the MPI for Spectroscopy (also in Göttingen), forming the MPI for Biophysical Chemistry. This was mainly initiated by Nobel Prize laureate Manfred Eigen , director of

1248-508: The MPI for Physical Chemistry. His vision of an interdisciplinary approach to biological research was decisive and the creative impulse for the development of the institute. In honour of Karl Friedrich Bonhoeffer, the new institute was named after him. Although the institute was dedicated to basic research – by virtue of the charter of the Max Planck Society – its policy was to encourage the transfer of numerous technological innovations to

1296-405: The U.S. Food and Drug Administration (FDA). In February 2020, Alnylam appointed former Sanofi CEO Olivier Brandicourt to its board of directors. In 2021, it was announced that Maraganore would step down as CEO, to be succeeded by the company's chief operating officer, Yvonne Greenstreet , on January 1, 2022. In December 2021, Alnylam submitted a clinical trial authorisation (CTA) application to

1344-429: The cell bodies of neurons must be conveyed outward to the distal synapses. This is accomplished via fast anterograde transport . It has been found that APP can mediate interaction between cargo and kinesin and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein. Additionally, it has been shown that

1392-462: The company's lead candidate in phase III studies was patisiran , a treatment targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR), in patients with the compromised nervous system condition of familial amyloidotic polyneuropathy (FAP). In August 2018, with its commercial name Onpattro , patisiran received the U.S. regulatory approval to treat polyneuropathy in patients with hereditary ATTR amyloidosis. In September 2023,

1440-473: The differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC. AβPP and its cleavage products do not promote

1488-429: The entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis . Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin , whose gene has been identified as

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1536-446: The independent Biomedizinische NMR Forschungs GmbH headed by Jens Frahm , which was founded in 1993. The focus of this association is the development and application of spatially resolved NMR techniques for non-invasive studies of the central nervous system in animals and humans. These innovative approaches allow for unique insights into the structure, metabolism and function of the intact living brain. Jens Frahm and his coworkers invented

1584-425: The institute can actively continue their research for a couple of years. The institute has undergone a permanent change in research with the closing of departments after their heads have retired and by continuously establishing new departments. Some of the former directors pursue their research even after their Emeritus Group has expired and can still be contacted at the institute (*). The institute also accommodates

1632-561: The institute – Stefan Hell , 2014; Erwin Neher and Bert Sakmann , 1991; and Manfred Eigen , 1967 – were awarded the Nobel Prize . The origins of the institute date to 1949. At that time, the Max Planck Society established the MPI for Physical Chemistry in Göttingen as a follow-up to the former Kaiser Wilhelm Institute for Physical Chemistry in Berlin. Karl-Friedrich Bonhoeffer , who had worked at

1680-419: The interaction between APP and kinesin is specific to the peptide sequence of APP. In a recent experiment involving transport of peptide-conjugated colored beads , controls were conjugated to a single amino acid, glycine , such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that

1728-436: The iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin ). The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with

1776-589: The isoform differentially expressed in the brain, is found between acidic region and E2 domain. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain, the copper-binding domain, the complete E1 domain and the E2 domain. Amyloid-beta precursor protein is highly versatile with several isoforms generated through alternative splicing of its mRNA. The primary isoforms include APP695, APP751, and APP770, differing in their inclusion of certain exons, mainly exon 7 and 8. APP695

1824-459: The isoform diversity of APP is essential for deciphering its various physiological and pathological roles. APP undergoes extensive post-translational modification including glycosylation , phosphorylation , sialylation , and tyrosine sulfation , as well as many types of proteolytic processing to generate peptide fragments. It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly

1872-449: The marketplace. As a consequence, many licensing agreements and start-up firms arose from research conducted at the institute, e. g. Lambda Physik (today part of Coherent), DeveloGen (today part of Evotec ) and Evotec . Research at the institute focuses on the fundamental mechanisms that regulate and control life processes: How is genetic information correctly translated into proteins? How do nerve cells communicate with each other? How

1920-503: The neuronal ratio of these isoforms have been associated with Alzheimer's disease. Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals . The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions. Mutations in critical regions of amyloid precursor protein, including

1968-476: The other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation. The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. The data indicate that this deficit in APP results from

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2016-479: The proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle . It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone , the adult equivalent of hCG, post- menopause and during andropause drives amyloid-β production and re-entry of post-mitotic neurons into

2064-453: The region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease. For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ. A mutation (A673T) in the APP gene protects against Alzheimer's disease. This substitution is adjacent to the beta secretase cleavage site and results in

2112-447: The same time the institute concentrates on developing novel measurement and analysis methods to provide a closer look into the world of molecules. The Max Planck Institute for Biophysical Chemistry currently encompasses 12 departments: The Max Planck Institute for Biophysical Chemistry is particularly engaged in the support of junior scientists. 20 independent research groups pursue their own research goals. After retiring, directors of

2160-414: The terminal COOH moiety of peptides is not sufficient to mediate transport. A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin , facilitating iron export through interaction with ferroportin ; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's. It has been shown that

2208-445: The three classical scientific disciplines – biology, physics and chemistry. Founded in 1971, its initial focus was on problems in physics in chemistry. It had undergone a continuous evolution manifested through an expanding range of core subjects and work areas such as neurobiology , biochemistry , and molecular biology . At the time of merger, 850 people worked at the institute, about half of them scientists. Four researchers working at

2256-709: Was modified to make it unique. In 2003, the firm merged with the German pharmaceutical company, Ribopharma AG. The newly formed company also received $ 24.6 million in funding from private-equity firms. On February 27, 2004, Alnylam Pharmaceuticals filed for an IPO . The company raised $ 26 million and began trading as ALNY on the Nasdaq stock exchange. In 2005, the company partnered with Medtronic to develop drug-device combinations to treat neurodegenerative disorders, and in 2006 with Biogen Idec to develop treatments of progressive multifocal leukoencephalopathy . In 2007, it entered into

2304-1544: Was opened in 2008 (in cooperation with the Max Planck Institute for Dynamics and Self-Organization). Amyloid-beta precursor protein 1AAP , 1AMB , 1AMC , 1AML , 1BA4 , 1BA6 , 1BJB , 1BJC , 1BRC , 1CA0 , 1HZ3 , 1IYT , 1MWP , 1OWT , 1QCM , 1QWP , 1QXC , 1QYT , 1TAW , 1TKN , 1X11 , 1Z0Q , 1ZJD , 2BEG , 2BP4 , 2FJZ , 2FK1 , 2FK2 , 2FK3 , 2FKL , 2FMA , 2G47 , 2IPU , 2LFM , 2LLM , 2LMN , 2LMO , 2LMP , 2LMQ , 2LOH , 2LP1 , 2OTK , 2R0W , 2WK3 , 2Y29 , 2Y2A , 2Y3J , 2Y3K , 2Y3L , 3AYU , 3DXC , 3DXD , 3DXE , 3GCI , 3IFL , 3IFN , 3IFO , 3IFP , 3JTI , 3KTM , 3L33 , 3L81 , 3MOQ , 3NYL , 3SV1 , 3U0T , 3UMH , 3UMI , 3UMK , 4HIX , 1ZE7 , 1ZE9 , 2LNQ , 2LZ3 , 2LZ4 , 2M4J , 2M9R , 2M9S , 2MGT , 2MJ1 , 2MPZ , 2MVX , 2MXU , 3BAE , 3BKJ , 3JQ5 , 3JQL , 3MXC , 3NYJ , 3OVJ , 3OW9 , 4JFN , 4M1C , 4MDR , 4NGE , 4OJF , 4ONF , 4ONG , 4PQD , 4PWQ , 4MVI , 4MVK , 4MVL , 4XXD , 5CSZ , 5AMB , 5AEF , 5AM8 , 5BUO , 5HOY , 5HOW , 5HOX , 5KK3 , 5C67 , 2NAO 351 11820 ENSG00000142192 ENSMUSG00000022892 P05067 P12023 NM_001136131 NM_001204301 NM_001204302 NM_001204303 NM_201413 NM_001385253 NM_001198823 NM_001198824 NM_001198825 NM_001198826 NM_007471 NP_001191230 NP_001191231 NP_001191232 NP_958816 NP_958817 NP_001185752 NP_001185753 NP_001185754 NP_001185755 NP_031497 Amyloid-beta precursor protein ( APP )

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