Pardi N.,University of Pennsylvania |
Secreto A.J.,University of Pennsylvania |
Shan X.,University of Pennsylvania |
Debonera F.,University of Pennsylvania |
And 13 more authors.
Nature Communications | Year: 2017
Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles. Systemic administration of 1.4 mg kg-1 of mRNA into mice results in ∼1/4170 μg ml-1 VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg-1 of mRNA into immunodeficient mice maintain trough VRC01 levels above 40 μg ml-1. Most importantly, the translated antibody from a single injection of VRC01 mRNA protects humanized mice from intravenous HIV-1 challenge, demonstrating that nucleoside-modified mRNA represents a viable delivery platform for passive immunotherapy against HIV-1 with expansion to a variety of diseases. © 2017 The Author(s).
Pardi N.,University of Pennsylvania |
Hogan M.J.,University of Pennsylvania |
Pelc R.S.,U.S. National Institutes of Health |
Muramatsu H.,University of Pennsylvania |
And 33 more authors.
Nature | Year: 2017
Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives. Therefore, the development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins. Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 μg was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA-LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV. © Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
News Article | March 2, 2017
Acuitas Therapeutics Inc., ein privates Biotechnologie-Unternehmen, das eine hochmoderne Lipidnanopartikel(LNP)-Abgabetechnik für Messenger-RNA (mRNA) entwickelt, hat heute die Veröffentlichung von Daten bekanntgegeben, die zeigen, dass mRNA, die breit neutralisierende Antikörper codiert und in einem Acuitas-LNP-Träger abgegeben wird, humanisierte Mäuse vor einer HIV-1-Infektion schützt. In einem heute in Nature Communications veröffentlichten Artikel zeigten Wissenschaftler und akademische Forscher von Acuitas unter der Leitung von Dr. Drew Weissman, MD, Professor für Infektionskrankheiten an der Perelman School of Medicine der Universität Pennsylvania, dass durch eine einzige Injektion mit mRNA-LNP, die den HIV-1-Antikörper VRC01 (1,4 mg/kg) codieren, nach 24 Stunden eine Plasma-Antikörper-Konzentration von etwa 170 µg/ml erreicht wurde. Des Weiteren wurde durch eine wöchentliche Verabreichung von 1 mg/kg mRNA-LNP eine Antikörperkonzentration mit einem Talspiegel von etwa 40 µg/ml beibehalten. Wichtig hierbei ist, dass eine einzige Injektion mit VRC01 mRNA-LNP humanisierte Mäuse auf dosisabhängige Weise vor einer intravenösen HIV-1-Übertragung schützte. "Diese neueste Veröffentlichung durch Dr. Weissman und seine Kollegen verdeutlicht das Potenzial der mRNA-LNP-Therapie als passive Immuntherapie gegen HIV-1 sowie möglicherweise gegen weitere Infektionskrankheiten. Zudem wird hierdurch das Konzept, die Leber als "Proteinfabrik" zu nutzen, sowie die Durchführbarkeit von wiederholten Dosierungen veranschaulicht", sagte Dr. Thomas Madden, Geschäftsführer und Vorstandsvorsitzender von Acuitas Therapeutics. Informationen zu Messenger-RNA (mRNA) Messenger-RNA ist ein natürliches Molekül, das Zellen die Herstellung von Proteinen ermöglicht. Informationen, die für ein spezifisches Protein codieren, sind in Genen im Zellkern enthalten. Diese Informationen werden in eine Nachricht (mRNA) transkribiert, die dann aus dem Kern wandert und in das spezifische Protein translatiert wird. Synthetische mRNA kann mithilfe von Acuitas-LNP-Trägern in eine Zelle eingebracht werden, um die Zelle zur Herstellung eines therapeutischen Proteins anzuweisen. Solche therapeutischen Proteine könnten ein fehlendes oder defektes Protein ersetzen, als Antikörper zum Schutz vor Infektion agieren oder eine schützende Immunantwort (d. h. eine Impfung) bereitstellen. Informationen zu Acuitas Therapeutics Acuitas Therapeutics ist ein privates Biotechnologie-Unternehmen mit Sitz in Vancouver, British Columbia, Kanada, das neuartige LNP-Träger für mRNA und andere Nukleinsäure-Therapeutika entwickelt, darunter eine Technologie, die unter beschränkter Lizenz von der Arbutus Biopharma Corporation entwickelt wird.
PubMed | University of Pennsylvania and Acuitas Therapeutics
Type: | Journal: Journal of controlled release : official journal of the Controlled Release Society | Year: 2015
In recent years, in vitro transcribed messenger RNA (mRNA) has emerged as a potential therapeutic platform. To fulfill its promise, effective delivery of mRNA to specific cell types and tissues needs to be achieved. Lipid nanoparticles (LNPs) are efficient carriers for short-interfering RNAs and have entered clinical trials. However, little is known about the potential of LNPs to deliver mRNA. Here, we generated mRNA-LNPs by incorporating HPLC purified, 1-methylpseudouridine-containing mRNA comprising codon-optimized firefly luciferase into stable LNPs. Mice were injected with 0.005-0.250mg/kg doses of mRNA-LNPs by 6 different routes and high levels of protein translation could be measured using in vivo imaging. Subcutaneous, intramuscular and intradermal injection of the LNP-encapsulated mRNA translated locally at the site of injection for up to 10days. For several days, high levels of protein production could be achieved in the lung from the intratracheal administration of mRNA. Intravenous and intraperitoneal and to a lesser extent intramuscular and intratracheal deliveries led to trafficking of mRNA-LNPs systemically resulting in active translation of the mRNA in the liver for 1-4 days. Our results demonstrate that LNPs are appropriate carriers for mRNA in vivo and have the potential to become valuable tools for delivering mRNA encoding therapeutic proteins.
News Article | March 2, 2017
Acuitas Therapeutics Inc., a private biotechnology company developing state-of-the-art lipid nanoparticle (LNP) delivery technology for messenger RNA (mRNA), announced today publication of data demonstrating that mRNA encoding a broadly neutralizing antibody delivered in an Acuitas LNP carrier protects humanized mice from HIV-1 challenge. In a paper published today in Nature Communications, Acuitas' scientists and academic researchers lead by Drew Weissman, MD, PhD, a professor of Infectious Diseases in the Perelman School of Medicine at the University of Pennsylvania showed that a single injection of mRNA-LNP encoding the anti-HIV-1 antibody VRC01 (1.4 mg/kg) resulted in plasma antibody concentrations of ~170 µg/mL at 24 hours. Further, weekly administrations of 1 mg/kg mRNA-LNP maintained trough antibody concentrations of ~40 µg/mL. Importantly a single injection of VRC01 mRNA-LNP protected humanized mice from an intravenous HIV-1 challenge in a dose-dependent manner. "This latest publication with Dr. Weissman and his colleagues illustrates the potential for mRNA-LNP therapeutics to provide passive immunotherapy against HIV-1 and potentially against other infectious diseases. In addition it exemplifies the concept of using the liver as a "protein factory" and the viability of repeat dosing" said Thomas Madden, Ph.D., President and Chief Executive Officer of Acuitas Therapeutics. About messenger RNA (mRNA) Messenger RNA is a natural molecule that allows cells to produce proteins. Information that codes for a specific protein is contained on genes in the cell nucleus. This information is transcribed into a message (mRNA), which then migrates out of the nucleus and is translated into the specific protein. Synthetic mRNA can be introduced into a cell using Acuitas LNP carriers to direct the cell to produce a therapeutic protein. Such therapeutic proteins could replace a missing or defective protein, be an antibody to protect against infection, or provide a protective immune response (i.e. a vaccine). About Acuitas Therapeutics Acuitas Therapeutics is a private biotechnology company located in Vancouver, British Columbia, Canada developing novel LNP carriers for mRNA and other nucleic acid therapeutics, including technology developed under limited license from Arbutus Biopharma Corporation.
Thess A.,CureVac GmbH |
Grund S.,CureVac GmbH |
Mui B.L.,Acuitas Therapeutics |
Hope M.J.,Acuitas Therapeutics |
And 3 more authors.
Molecular Therapy | Year: 2015
Being a transient carrier of genetic information, mRNA could be a versatile, flexible, and safe means for protein therapies. While recent findings highlight the enormous therapeutic potential of mRNA, evidence that mRNA-based protein therapies are feasible beyond small animals such as mice is still lacking. Previous studies imply that mRNA therapeutics require chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system. Here we show that chemically unmodified mRNA can achieve those goals as well by applying sequence-engineered molecules. Using erythropoietin (EPO) driven production of red blood cells as the biological model, engineered Epo mRNA elicited meaningful physiological responses from mice to nonhuman primates. Even in pigs of about 20 kg in weight, a single adequate dose of engineered mRNA encapsulated in lipid nanoparticles (LNPs) induced high systemic Epo levels and strong physiological effects. Our results demonstrate that sequence-engineered mRNA has the potential to revolutionize human protein therapies. © The American Society of Gene & Cell Therapy.
PubMed | University of British Columbia, Acuitas Therapeutics and Alnylam Pharmaceuticals
Type: | Journal: Molecular therapy. Nucleic acids | Year: 2013
Lipid nanoparticles (LNPs) encapsulating short interfering RNAs that target hepatic genes are advancing through clinical trials, and early results indicate the excellent gene silencing observed in rodents and nonhuman primates also translates to humans. This success has motivated research to identify ways to further advance this delivery platform. Here, we characterize the polyethylene glycol lipid (PEG-lipid) components, which are required to control the self-assembly process during formation of lipid particles, but can negatively affect delivery to hepatocytes and hepatic gene silencing in vivo. The rate of transfer from LNPs to plasma lipoproteins in vivo is measured for three PEG-lipids with dialkyl chains 14, 16, and 18 carbons long. We show that 1.5mol % PEG-lipid represents a threshold concentration at which the chain length exerts a minimal effect on hepatic gene silencing but can still modify LNPs pharmacokinetics and biodistribution. Increasing the concentration to 2.5 and 3.5mol % substantially compromises hepatocyte gene knockdown for PEG-lipids with distearyl (C18) chains but has little impact for shorter dimyristyl (C14) chains. These data are discussed with respect to RNA delivery and the different rates at which the steric barrier disassociates from LNPs in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e139; doi:10.1038/mtna.2013.66; published online 17 December 2013.
PubMed | Acuitas Therapeutics and CureVac GmbH
Type: Journal Article | Journal: Molecular therapy : the journal of the American Society of Gene Therapy | Year: 2015
Being a transient carrier of genetic information, mRNA could be a versatile, flexible, and safe means for protein therapies. While recent findings highlight the enormous therapeutic potential of mRNA, evidence that mRNA-based protein therapies are feasible beyond small animals such as mice is still lacking. Previous studies imply that mRNA therapeutics require chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system. Here we show that chemically unmodified mRNA can achieve those goals as well by applying sequence-engineered molecules. Using erythropoietin (EPO) driven production of red blood cells as the biological model, engineered Epo mRNA elicited meaningful physiological responses from mice to nonhuman primates. Even in pigs of about 20kg in weight, a single adequate dose of engineered mRNA encapsulated in lipid nanoparticles (LNPs) induced high systemic Epo levels and strong physiological effects. Our results demonstrate that sequence-engineered mRNA has the potential to revolutionize human protein therapies.
News Article | March 2, 2017
VANCOUVER, March 2, 2017 /PRNewswire/ - Acuitas Therapeutics Inc., a private biotechnology company developing state-of-the-art lipid nanoparticle (LNP) delivery technology for messenger RNA (mRNA), announced today publication of data demonstrating that mRNA encoding a broadly neutralizing...