Rottiers V.,Massachusetts General Hospital |
Rottiers V.,Harvard University |
Obad S.,Santaris Pharma |
Petri A.,Santaris Pharma |
And 28 more authors.
Science Translational Medicine | Year: 2013
MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base pairing with 3′ untranslated regions, primarily via seed sequences (nucleotides 2 to 8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy of different miRNAs sharing the same seed sequence and the challenge of simultaneously targeting miRNAs that differ significantly in nonseed sequences complicate therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and nonhuman primates, have not been determined. We show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant nonhuman primates results in derepression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein cholesterol, and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against an miRNA family in a nonhuman primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.
PubMed | National Taiwan University, OPKO Health, Rxgen, Inc., University of Miami and National Taiwan University Hospital
Type: | Journal: EBioMedicine | Year: 2016
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.
Sidman R.L.,Beth Israel Deaconess Medical Center |
Li J.,Beth Israel Deaconess Medical Center |
Lawrence M.,Rxgen, Inc. |
Lawrence M.,St Kitts Biomedical Research Foundation |
And 7 more authors.
Science Translational Medicine | Year: 2015
Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and mainly VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. We have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys) [D(CLPRC)], and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors VEGFR-1 and neuropilin-1 (NRP-1). Delivery of Vasotide via either eye drops or intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of ROP decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less-invasive applications to combat pathological angiogenesis in retinal disorders.
Liddie S.,St Kitts Biomedical Research Foundation |
Goody R.J.,Rxgen, Inc. |
Valles R.,St Kitts Biomedical Research Foundation |
Lawrence M.S.,Rxgen, Inc.
Journal of Medical Primatology | Year: 2010
Background Hematology and clinical chemistry (HCC) reference values are critical in veterinary practice and in vivo pre-clinical research, enabling detection of health abnormalities, response to therapeutic intervention or adverse toxicological effects, as well as monitoring of clinical management.Methods In this report, reference ranges for 46 HCC parameters were characterized in 331 wild-caught and colony-bred African green monkeys. Effects of sex, weight and duration of captivity were determined by one-way analysis of variance.Results Significant sex differences were observed for several HCC parameters. Significant differences were also observed for select HCC variables between newly caught animals and those held in captivity for 1-12months or longer.Conclusions Comparison of this data with other non-human primate species and humans highlights similarities and disparities between species. Potential causes of interpopulation variability and relevance to the use of the African green monkey as a non-human primate model are discussed. © 2010 John Wiley & Sons A/S.
News Article | December 8, 2016
NEW HAVEN, Conn. & CAMBRIDGE, Mass.--(BUSINESS WIRE)--RxGen, a translational R&D company, and LabCentral, a first-of-its-kind shared laboratory space designed as a launchpad for high-potential life-sciences and biotech startups, today announced that RxGen has become a LabCentral Gold sponsor. “We are thrilled to welcome RxGen to LabCentral as one of our newest Gold sponsors. Our number one focus is to bring people, ideas, and resources together to assure that the most innovative and promising solutions are advanced efficiently and effectively,” said LabCentral's Co-Founder and President, Johannes Fruehauf, M.D., Ph.D. “A critical ingredient includes access to knowhow and resources within and beyond the walls of LabCentral. By their sponsorship and direct engagement with the LabCentral community, RxGen will bring both.” “We share LabCentral’s commitment to providing the best possible environment to assure the success of promising therapeutic strategies,” said RxGen CEO, Matthew Lawrence, M.D., Ph.D. “We hope to contribute to that ecosystem by making our scientists, research platform, and unique preclinical research capabilities available to help achieve important milestones early and effectively.” RxGen’s sponsorship will connect LabCentral scientists and alumni to a translational research team positioned to help propel concepts and candidates to clinical success through early and sustained engagement, and alignment of development strategy with the most predictive possible preclinical modeling and analysis. RxGen is a translational research company devoted to developing and providing predictive preclinical research models to accelerate therapeutic candidate development, and reduce the risk of clinical failure. Formed in 2002, RxGen engages with leading academic, biotechnology, and pharmaceutical sponsors and collaborators to design and execute a wide range of preclinical studies and translational research programs across various therapeutic areas. Application of RxGen’s unique translational capabilities is enabled by flexible scientific and commercial interactions that span contract research services, research collaborations and R&D partnering agreements. A 28,000 square-foot facility in the heart of the Kendall Square, Cambridge, biotech innovation hub, LabCentral is a first-of-its-kind shared laboratory space designed as a launchpad for high-potential life-sciences and biotech startups. It offers fully permitted laboratory and office space for early-stage companies comprising approximately 125 scientists and entrepreneurs. LabCentral provides first-class facility and administrative support, skilled laboratory personnel, a domain-relevant expert speaker series ‒ as well as the other critical services and support that startups need to begin laboratory operations on day one. A private, nonprofit institution, LabCentral was funded in part by a $5 million grant from the Massachusetts Life Sciences Center, with support from its real-estate partner, MIT. Founding sponsors include Triumvirate Environmental and Johnson & Johnson Innovation.
Goody R.J.,Rxgen, Inc. |
Hu W.,Bausch and Lomb Inc. |
Shafiee A.,Bausch and Lomb Inc. |
Struharik M.,Rxgen, Inc. |
And 3 more authors.
Experimental Eye Research | Year: 2011
We developed and validated a new nonhuman primate model of laser-induced choroidal neovascularization (CNV) that addresses study design limitations prevalent in laser-induced CNV-based efficacy studies. Laser-induced Bruch's membrane disruption triggers CNV and has been widely utilized in animals to model neovascular (" wet" ) age-related macular degeneration (AMD). Despite widespread use of the approach, detailed assessment of experimental parameters and their influence on pathophysiological endpoints critical for disease modeling has been extremely limited and largely based on anecdotal observations. We evaluated laser power parameters and endpoint measures to optimize methods for CNV formation and quantification to facilitate drug efficacy screening in African green monkeys. Six laser spots of 350, 550, 750, 950 or 1500 mW laser power were positioned bilaterally 1.5 disc diameters from the fovea, within the macula. Fluorescein angiograms were collected 3-5 weeks later and scored by trained masked investigators using graded (I-IV) and densitometric methods. Histopathology assessments were also performed, including determination of CNV area. Test system sensitivity to angiogenesis inhibition was subsequently assessed by evaluating the effect of intravitreal bevacizumab (Avastin) pretreatment (one day prior to laser photocoagulation) on incidence of CNV. Grade III and grade IV lesions were considered clinically relevant, demonstrating early hyperfluorescence and late leakage within or beyond the lesion borders. By 4 weeks post-laser all treatment groups demonstrated evidence of grade III lesions with greatest incidence observed in lesions induced by 750 and 950 mW laser power (72.9% and 69.4% respectively). Grade IV lesions were confined to eyes receiving 550 mW laser power or higher, with highest incidence of grade IV lesions observed in eyes receiving 950 (19.4%) and 1500 mW (31%) laser spots, incidence peaking 4 weeks post-laser photocoagulation. Densitometric analyses of angiograms corroborated visual scoring. Bevacizumab completely abolished grade IV lesion development and significantly lowered lesion fluorescein signal intensity (P < 0.0001) and CNV area (P = 0.038) compared to vehicle-treated controls. Our studies demonstrate that laser power of 950-1500 mW and angiography analysis 4 weeks post-laser are optimal parameters to evaluate treatment effects on CNV induction following laser photocoagulation. Bevacizumab significantly attenuated CNV development, as determined by fluorescein angiography and histopathology assessments in this model, supporting the application of African green monkeys in preclinical modeling of CNV. Laser parameters and time points for therapeutic dosing and angiography endpoints are critical factors to the laser-induced CNV model and must be validated for robust assessment of efficacy. The newly optimized nonhuman primate model described will facilitate preclinical efficacy assessments of novel therapeutics for CNV. © 2011 Elsevier Ltd.
PubMed | Materials Hospital, Ross University School of Medicine, Imperial College London, Trinity College Dublin and 5 more.
Type: | Journal: Scientific reports | Year: 2017
The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemms canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.