A5060764236- Virus-based gene therapy research
- Herpesvirus Infections and Treatments
- Cytomegalovirus and herpesvirus research
- interferon and immune responses
- Cancer Immunotherapy and Biomarkers
- Toxoplasma gondii Research Studies
- Ubiquitin and proteasome pathways
- Viral Infectious Diseases and Gene Expression in Insects
- CRISPR and Genetic Engineering
- HIV Research and Treatment
- Cancer Research and Treatments
- Neuroblastoma Research and Treatments
- Cytokine Signaling Pathways and Interactions
- CAR-T cell therapy research
- Viral gastroenteritis research and epidemiology
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Diabetes and associated disorders
- Radiopharmaceutical Chemistry and Applications
- Endoplasmic Reticulum Stress and Disease
- Viral-associated cancers and disorders
- Monoclonal and Polyclonal Antibodies Research
- Medical Imaging Techniques and Applications
- RNA Interference and Gene Delivery
- Blood groups and transfusion
Harvard University
2004-2021
Ultragenyx Pharmaceutical (United States)
2021
Dimension Therapeutics (United States)
2016
New England Biolabs (United States)
2015
Whitehead Institute for Biomedical Research
2006-2009
Massachusetts Institute of Technology
2007
Abstract Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed safety and tolerability plus spartalizumab (PDR001), humanized IgG4 antibody against PD-1, 106 patients with advanced solid tumors or lymphomas. Patients Methods: were treated weekly intratumoral...
Significance Congenital cytomegalovirus (CMV) is the leading infectious cause of childhood hearing loss and brain damage worldwide. Yet, despite its high prevalence ranking as a top priority for vaccine development, immune correlates protection that could guide development remain undefined. Using novel nonhuman primate model congenital CMV transmission, we demonstrate critical role maternal CD4 + T cells in induction protective responses prevent fetal demise. In addition to establishing...
The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinating activity embedded in it. All members the Herpesviridae contain homologue HSV-1 N-terminal segments which show perfect conservation those residues implicated catalysis. For murine cytomegalovirus and Epstein-Barr virus, chosen as representatives beta- gammaherpesvirus subfamilies, respectively, we here that homologous modules indeed display vitro. this throughout all subfamilies is...
ABSTRACT Proteins associated with the murine cytomegalovirus (MCMV) viral particle were identified by a combined approach of proteomic and genomic methods. Purified MCMV virions dissociated complete denaturation subjected to either separation sodium dodecyl sulfate-polyacrylamide gel electrophoresis in-gel digestion or treated directly in-solution tryptic digestion. Peptides separated nanoflow liquid chromatography analyzed tandem mass spectrometry (LC-MS/MS). The MS/MS spectra obtained...
We show here that the high-molecular-weight protein (HMWP or pUL48; 253 kDa) of human cytomegalovirus (HCMV) is a functionally competent deubiquitinating protease (DUB). By using suicide substrate probe specific for ubiquitin-binding cysteine proteases (DUB probe) to screen lysates HCMV-infected cells, we found just one infected-cell-specific DUB. Characteristics this protein, including its large size, expression at late times infection, presence in extracellular virus particles, and...
The herpesvirus ubiquitin-specific protease (USP) family, whose founding member was discovered as a domain embedded in the large tegument protein of herpes simplex virus 1 (HSV-1), is conserved across all members Herpesviridae. Whether this conservation indicative an essential function enzyme vivo has not yet been established. As reported here, USP activity Marek's disease (MDV), tumorigenic alphaherpesvirus. A single amino acid substitution that abolishes MDV diminishes replication vivo,...
Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention HIV-1 infection. The immunoglobulin G (IgG)1 subtype usually selected this application, because it efficiently mediates antibody effector functions has somewhat longer half-life. However, use IgG1-Fc been associated with generation anti-drug (ADAs) that correlate loss expression. In contrast, we have shown expression antibody-like molecule eCD4-Ig bearing...
AAV-expressed eCD4-Ig protects rhesus macaques from SIVmac239.
Recent studies have demonstrated that the signaling activity of cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety posttranslational modifications (PTMs) to fine-tune antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination RIG-I caspase activation and recruitment domains (CARDs) catalyzed TRIM25 or other E3 ligases activates RIG-I, phosphorylation at S8 T170 represses signal transduction preventing TRIM25-RIG-I interaction...
ABSTRACT Murine gammaherpesvirus 68 (MHV-68) contains a ubiquitin (Ub)-specific cysteine protease (USP) domain embedded within the large tegument protein ORF64, as do all other herpesviruses. The biological role of this is still unclear, but for alphaherpesvirus Marek's disease virus, its USP involved in T-cell lymphoma formation. We here study MHV-68 USP, encoded by ORF64. By constructing mutant virus with single cysteine-to-alanine replacement active site we demonstrate that activity ORF64...
Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is general consensus on inclusion and exclusion criteria each these trials, the conditions under which infused vary significantly. In this study, we evaluated impact intravenous infusion rate AAV8 vector cynomolgus macaques transgene expression, clearance from circulation, potential activation innate immune system. The dose terms genome copies per kilogram...
The combination of loss habitat, human population encroachment, and increased demand select nonhuman primates for biomedical research has significantly affected populations. There remains a need knowledge expertise in understanding background findings as related to the age, source, strain, disease status primates. In particular, safety/biomedical studies, broader documentation lesions would help clarify from drug-related findings. A workshop minisymposium on spontaneous diseases were...
Abstract Purpose: Due to profound clinical successes observed with radioligand therapies (RLT) across multiple cancers coupled advances in drug handling and delivery logistics recently, trials investigating RLTs are on the rise. Ionizing radiation produced by radioisotopes linked antibodies causes double-stranded breaks either directly or via generation of reactive oxygen species. This type DNA damage is associated an increase proteins mediating cell cycle arrest (e.g., p21/CIP1) repairing...
<div>AbstractPurpose:<p>The stimulator of IFN genes (STING) is a transmembrane protein that plays role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed safety and tolerability plus spartalizumab (PDR001), humanized IgG4 antibody against PD-1, 106 patients with advanced solid tumors or lymphomas.</p>Patients...
Hemophilia A, a bleeding disorder, affects 1:5,000 males and is caused by deficiency of human blood coagulation factor VIII (hFVIII). Studies in mice macaques identified AAVhu37.E03.TTR.hFVIIIco-SQ.PA75 as clinical candidate gene therapy vector to treat hemophilia A. In this study, we sought determine the minimally effective dose (MED) A mouse model. Mice received one four doses (3 × 1011-1 1013 genome copies [GCs]/kg) via intravenous tail vein injection; cohort vehicle control. Animals were...
Despite the availability of safe and effective recombinant FIX therapeutics, patients with Hemophilia B could obtain additional clinical benefit by having longer-acting therapeutic options. Although protein therapies are becoming available, ultimate long-acting therapy be provided a gene approach, for example rAAV vectors encoding FIX. Promising data has been generated over last few years in an academic setting, but these results must replicated extended commercial setting new to become...
<p>Supplementary tables and figures with legends</p>
<div>AbstractPurpose:<p>The stimulator of IFN genes (STING) is a transmembrane protein that plays role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed safety and tolerability plus spartalizumab (PDR001), humanized IgG4 antibody against PD-1, 106 patients with advanced solid tumors or lymphomas.</p>Patients...