North Brunswick, NJ, United States
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Weisleder N.,Robert Wood Johnson Medical School | Weisleder N.,Trim-Edicine, Inc. | Takizawa N.,Trim-Edicine, Inc. | Lin P.,Robert Wood Johnson Medical School | And 18 more authors.
Science Translational Medicine | Year: 2012

Mitsugumin 53 (MG53), a muscle-specific TRIM family protein, is an essential component of the cell membrane repair machinery. Here, we examined the translational value of targeting MG53 function in tissue repair and regenerative medicine. Although native MG53 protein is principally restricted to skeletal and cardiac muscle tissues, beneficial effects that protect against cellular injuries are present in nonmuscle cells with overexpression of MG53. In addition to the intracellular action of MG53, injury to the cell membrane exposes a signal that can be detected by MG53, allowing recombinant MG53 protein to repair membrane damage when provided in the extracellular space. Recombinant human MG53 (rhMG53) protein purified from Escherichia coli fermentation provided dose-dependent protection against chemical, mechanical, or ultraviolet-induced damage to both muscle and nonmuscle cells. Injection of rhMG53 through multiple routes decreased muscle pathology in the mdx dystrophic mouse model. Our data support the concept of targeted cell membrane repair in regenerative medicine, and present MG53 protein as an attractive biological reagent for restoration of membrane repair defects in human diseases.


Cao C.-M.,Peking University | Zhang Y.,Peking University | Weisleder N.,Robert Wood Johnson Medical School | Weisleder N.,Trim-Edicine, Inc. | And 15 more authors.
Circulation | Year: 2010

Background-Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3β [GSK3β] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood. Methods and Results-In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/reperfusion-induced decrease in MG53 expression. MG53 deficiency increases myocardial vulnerability to ischemia/reperfusion injury and abolishes IPC protection. Overexpression of MG53 attenuates whereas knockdown of MG53 enhances hypoxia-and H2O2-induced cardiomyocyte death. The cardiac protective effects of MG53 are attributable to MG53-dependent interaction of caveolin-3 with phosphatidylinositol 3 kinase and subsequent activation of the reperfusion injury salvage kinase pathway without altering the survivor activating factor enhancement pathway. ConclusionS-: These results establish MG53 as a primary component of the cardiac IPC response, thus identifying a potentially important novel therapeutic target for the treatment of ischemic heart disease. © 2010 American Heart Association, Inc.


Moloughney J.G.,UMDNJ Robert Wood Johnson Medical School | Weisleder N.,Ohio State University | Weisleder N.,Trim-Edicine, Inc.
Recent Patents on Biotechnology | Year: 2012

Maintenance of the integrity of the plasma membrane is essential for maintenance of cellular function and prevention of cell death. Since the plasma membrane is frequently exposed to a variety of mechanical and chemical insults the cell has evolved active processes to defend against these injuries by resealing disruptions in the plasma membrane. Cell membrane repair is a conserved process observed in nearly every cell type where intracellular vesicles are recruited to sites of membrane disruption where they can fuse with themselves or the plasma membrane to create a repair patch. When disruptions are extensive or there is an underlying pathology that reduces the membrane repair capacity of a cell this defense mechanism may prove insufficient and the cell could die due to breakdown of the plasma membrane. Extensive loss of cells can compromise the integrity and function of tissues and leading to disease. Thus, methods to increase membrane resealing capacity could have broad utility in a number of disease states. Efforts to find reagents that can modulate plasma membrane reseal found that specific tri-block copolymers, such as poloxamer 188 (P188, or Pluronic F68), can increase the structural stability and resealing of the plasma membrane. Here we review several current patents and patent applications that present inventions making use of P188 and other copolymers to treat specific disease states such as muscular dystrophy, heart failure, neurodegenerative disorders and electrical injuries, or to facilitate biomedical applications such as transplantation. There appears to be promise for the application of poloxamers in the treatment of various diseases, however there are potential concerns with toxicity with long term application and bioavailability in some cases. © 2012 Bentham Science Publishers.


De G.,Ohio State University | Ko J.-K.,Rutgers University | Ko J.-K.,Mutagenex Inc. | Tan T.,Trim-Edicine, Inc. | And 5 more authors.
Oncotarget | Year: 2014

Amphipathic tail-anchoring peptide (ATAP) derived from the human anti-apoptotic protein Bfl-1 is a potent inducer of apoptosis by targeting mitochondria permeability transition. By linking ATAP to an internalizing RGD peptide (iRGD), selective targeting for ATAP to tumor cell was achieved. Confocal fluorescence microscopy showed that ATAP-iRGD could penetrate into cancer cells and distribute along the mitochondria network. ATAP-iRGD triggered mitochondria-dependent cell death through release of cytochrome c. In an effort to promote ATAP-iRGD physiochemical properties to approach clinic application, amino acid substitution and chemical modification were made with ATAP-iRGD to improve its bioactivity. One of these modified peptides, ATAP-iRGD-M8, was with improved stability and aqueous solubility without compromising in vitro cytotoxicity in cultured cancer cells. In vivo xenograft studies with multiple prostate cancer cell lines showed that intravenous administration of ATAP-iRGD-M8 suppressed tumor growth. Toxicological studies revealed that repetitive intravenous administration of ATAP-iRGD-M8 did not produce significant toxicity in the SV129 mice. Our data suggest that ATAP-iRGD-M8 is a promising agent with high selectivity and limited systemic toxicity for prostate cancer treatment.


PubMed | Trim-Edicine, Inc., Central Connecticut State University, Ohio State University, Chongqing Medical University and Davis Heart and Lung Research Institute
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

Cell membrane repair is an important aspect of physiology, and disruption of this process can result in pathophysiology in a number of different tissues, including wound healing, chronic ulcer and scarring. We have previously identified a novel tripartite motif family protein, MG53, as an essential component of the cell membrane repair machinery. Here we report the functional role of MG53 in the modulation of wound healing and scarring. Although MG53 is absent from keratinocytes and fibroblasts, remarkable defects in skin architecture and collagen overproduction are observed in mg53(-/-) mice, and these animals display delayed wound healing and abnormal scarring. Recombinant human MG53 (rhMG53) protein, encapsulated in a hydrogel formulation, facilitates wound healing and prevents scarring in rodent models of dermal injuries. An in vitro study shows that rhMG53 protects against acute injury to keratinocytes and facilitates the migration of fibroblasts in response to scratch wounding. During fibrotic remodeling, rhMG53 interferes with TGF--dependent activation of myofibroblast differentiation. The resulting down-regulation of smooth muscle actin and extracellular matrix proteins contributes to reduced scarring. Overall, these studies establish a trifunctional role for MG53 as a facilitator of rapid injury repair, a mediator of cell migration, and a modulator of myofibroblast differentiation during wound healing. Targeting the functional interaction between MG53 and TGF- signaling may present a potentially effective means for promoting scarless wound healing.


Alloush J.,Ohio State University | Weisleder N.,Ohio State University | Weisleder N.,Trim-Edicine, Inc.
JAMA Neurology | Year: 2013

Muscular dystrophy represents a major unmet medical need; only palliative treatments exist for this group of debilitating diseases. Because multiple forms of muscular dystrophy arise from compromised sarcolemmal membrane integrity, a therapeutic approach that can target this loss of membrane function could be applicable to a number of these distinct diseases. One promising therapeutic approach involves the process the cell uses to repair injuries to the plasma membrane. Recent discoveries of genes associated with the membrane repair process provide an opportunity to promote this process as a way to treat muscular dystrophy. One such gene is mitsugumin 53 (MG53), a member of the tripartite motif (TRIM) family of proteins (TRIM72), which is an essential component of the membrane repair pathwayin muscle. Recent results indicate that MG53/TRIM72 protein can be directly applied as a therapeutic agent to increase membrane repair capacity of many cell types and treat some aspects of the disease in mouse models of muscular dystrophy. There is great potential for the use of recombinant human MG53 in treating muscular dystrophy and other diseases in which compromised membrane integrity contributes to the disease. Other TRIM familyproteins may provide additional targets for therapeutic intervention in similar disease states.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.41M | Year: 2012

DESCRIPTION (provided by applicant): SBIR 1R43AR060019 Phase II application: Protein Therapeutics for Muscular Dystrophy Principal Investigator: Takizawa, Norio Project Summary: This application requests for a Phase II project for our initial SBIR grant addressing the use of a novel protein therapeutic agent, MG53, for the treatment of muscular dystrophy (1R43AR060019). Our Phase I studies established manufacturing and formulation conditions, and provided significant proof- of-concept data for theuse of MG53 in treating muscular dystrophy. This Phase II application proposed additional proof-of concept experiments in multiple dystrophy models (mouse, dog) and critical toxicology studies. This proposal will directly target the muscular dystrophies,a family of geneti disorders that generally include progressive muscle weakness due to degeneration of the muscle fibers that is linked to either fragility of the membranes that surround muscle cells or a compromised ability to reseal those membranes. An emerging concept in recent biomedical research establishes that intrinsic membrane repair/regeneration is a fundamental aspect of normal physiology and that disruption of this repair function underlies the progression of many human diseases, including muscular dystrophy. A therapeutic approach to increase the capacity of muscle cells to reseal their membranes following physiological levels of mechanical stress could address both of these mechanisms leading to improvement of the regenerative capacity in muscular dystrophy. Attempts to produce therapeutics targeting this unmet medical need have been complicated by the lack of knowledge of the molecular components involved. Recent studies show that MG53, a muscle-specific TRIM-family protein, plays an essentialrole in protection of skeletal and cardiac muscle cells against various types of acute injury or chronic physiological stresses. MG53 ablation results in defective sarcolemmal membrane repair with progressive muscle pathology. In an effort to translate these basic science findings into therapeutic interventions for human diseases, we have formed a biotechnology company named TRIM-edicine, Inc, based on intellectual properties discovered at UMDNJ-Robert Wood Johnson Medical School. Our research and development effort at TRIM-edicine during Phase I of this SBIR project has established methods to produce large quantities of recombinant MG53 protein purified from E. coli that retains efficient membrane repair function. Furthermore, we produced in vivo animal model data using dystrophic mdx mice to show that intravenous (IV) delivery of recombinant MG53 can repair membrane damage to skeletal muscle and ameliorate the pathology associated with muscular dystrophy. Additional in vivo data show that repetitive IV-injections of recombinant human MG53 to mice are safe and do not produce adverse effects. Other studies showed that subcutaneous injection of MG53 can be effective for therapeutic approaches as well. This project will leverage the expertise at TRIM-edicine in biologic drug development to pursue necessary studies for development of recombinant MG53 in treatment of muscular dystrophy to allow for the filing of an Investigational New Drug (IND) application with the Food and Drug Administration (FDA). This PhaseII continuation project will involve a collaborative effort between TRIM-edicine and the University of North Carolina to pursue the proof-of-principle studies for the therapeutic application of MG53 in treatment of muscular dystrophy using the golden retriever model of muscular dystrophy. First, we will produce sufficient amount of recombinant dog MG53 proteins following our documented Chemical Manufacture Control (CMC) protocols. Second, we will test the efficacy and safety of the dog MG53 protein in reducing muscular pathology using a golden retriever with muscular dystrophy (GRMD) dog model. Third, upon completion of the in vivo animal model studies, the selection of animal species for the toxicology studies will be determined upon consultation with FDA in a pre-IND meeting. Completion of the safety/toxicology evaluations will provide the final step in preparation for filing of an IND application testing the use of recombinant MG53 in treatment of muscular dystrophy in human patients. PUBLIC HEALTH RELEVANCE: SBIR 1R43AR060019 Phase II application: Protein Therapeutics for Muscular Dystrophy Principal Investigator: Takizawa, Norio Project Narrative: Muscular dystrophies are severe genetic disorders that are associated with defects in muscle cell membrane integrity or a reduced capacity for muscle to repair damage that occurs during normal contraction. Attempts to produce therapeutics targeting this unmet medical need have been complicated by the lack of knowledge of the basic biology of cell membrane repair. The discovery of MG53 as a key component of the muscle membrane repair machinery has opened a new therapeutic approach for treatment of muscular dystrophy. The development effort proposed in this project will generate the proof-of principle data and the safety evaluation for using recombinant MG53 protein as a therapeutic agent for treatment of muscular dystrophy.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2014

DESCRIPTION (provided by applicant): While organ transplantation is a vital last resort therapy to treat patients with end-organ failure of the lung there is a growing waiting list of patients who are eligible for transplants as the number of suitable donor organs fall far short of the demand for these lifesaving procedures. Improving the preservation of donated organs so that a greater percentage would remain viable for use in transplant procedures represents an important area of unmet medical need in theUnited States. An agent to reduce ischemic damage to organs during transport will represent a technology that would enhance the protection of existing donors, expand the time window for surgical implementation, and potentially resuscitate marginal organs which could then be transplanted. The goal of this application is to examine the use of a tissue repair protein named MG53 in organ preservation for lung transplantation. Research and development efforts at TRIM-edicine have established that the recomb


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 833.69K | Year: 2016

Project Summary This direct Phase II SBIR proposal focuses on the development of recombinant human MG rhMG a novel tissue repair protein as a therapeutic candidate targeting injury of renal epithelium to protect against acute kidney injury AKI AKI is commonly encountered in the hospital and outpatient settings and is associated with a high rate of mortality Currently there is no effective means for preventing or treating AKI MG is a member of the TRIM family proteins that participates in repair of injury to the cell membrane and a vital component for reno protection under both physiologic and pathophysiologic settings Research and development effort at TRIM edicine a university spin off biotechnology company has established the following proof of concept data supporting rhMG as a potential therapeutic reagent for AKI First the chemistry manufacture and control CMC process for rhMG has been established that allows for scale up production of rhMG to support our pre clinical and future clinical studies Second preliminary toxicological studies in rodent and dog models support the safety for systemic application of rhMG Third transgenic mice with sustained elevation of MG in the bloodstream are healthy with enhanced lifespan and display remarkable tissue healing capacity Fourth pilot study with a canine model of AKI shows that prophylactic administration of rhMG can preserve kidney function following ischemia reperfusion injury Studies proposed in this SBIR project involve joint development efforts between TRIM edicine and The Ohio State University aiming to accomplish the IND enabling studies for developing rhMG as an injectable therapeutics for AKI treatment Five milestones with deliverable criteria are proposed in this application to complete the CMC for producing sufficient rhMG protein to support pre clinical toxicological and human clinical trials Milestone to develop assays for quality control of rhMG Milestone to establish the pharmacodynamic property of rhMG in the canine model of AKI Milestone to conduct safety and toxicological evaluation of rhMG per FDA guidance Milestone and to assemble IND for rhMG in AKI treatment Milestone Completion of these milestones will enable us to file an IND application to the FDA for initiating a Phase clinical trial for conducting an ascending dose study of the safety of a single intravenous infusion of rhMG in human subjects with stable ischemic heart diseases who are at risk of developing AKI during cardiothoracic surgery NARRATIVE Development of a therapeutic approach to ameliorate renal damage from acute kidney injury represents an important area of biomedical and clinical research The lead molecule for this application is MG a novel tissue repair gene Fulfillment of the studies proposed here aid the pre clinical and clinical development of this molecule a potential viable option for the treatment of acute kidney injury We have clearly defined the measurable goals that we plan to achieve in this grant proposal


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2010

DESCRIPTION (provided by applicant): Defective membrane repair is associated with the progression of muscular dystrophy that is linked to mutations in caveolin-3 (Cav3) and dysferlin in human patients. Several other forms of muscular dystrophy, including Duchenne muscular dystrophy and dystrophy arising from mutations in the dystroglycan complex have been linked to membrane fragility. Compromised membrane repair and increased membrane fragility are distinct mechanisms leading to increased muscle fiber death, as evidenced by the additive nature of these two pathways. A therapeutic approach to increase the capacity of muscle cells to reseal their membranes following physiological levels of mechanical stress could address both of these mechanisms leading to improvement of the regenerative capacity in muscular dystrophy. Attempts to produce therapeutics targeting membrane resealing have been complicated by the lack of knowledge of the molecular components involved. Recent studies show that Mitsuguimin 53 (MG53), a muscle-specific TRIM-family protein (TRIM72), is an essential component of the acute membrane repair machinery. MG53 acts as a sensor of oxidation to nucleate recruitment of intracellular vesicles to the injury site for membrane patch formation. MG53 can interact with dysferlin to facilitate its membrane repair function, and the membrane trafficking function of MG53 can be modulated through a functional interaction with Cav3. Our data indicate that a molecular complex formed by MG53, dysferlin and Cav3 is essential for repair of muscle membrane damage, thus providing a therapeutic target for treatment of muscular and cardiovascular diseases. In an effort to translate these basic science findings into therapeutic interventions for human diseases, we have formed a biotechnology company named TRIM-edicine, Inc, based on intellectual properties discovered in at UMDNJ-Robert Wood Johnson Medical School. Our research and development effort at TRIM-edicine has provided extensive studies to show that recombinant MG53 purified from E. coli retains efficient membrane repair function, supporting the therapeutic value of targeting MG53 in muscular dystrophy and other human diseases. We have preliminary in vivo animal model data to show that intra-muscular delivery of recombinant MG53 can ameliorate cardiotoxin-induced damage to the muscle fibers. This project will comprise an effort by TRIM-edicine that will leverage our expertise to pursue the proof-of-principle studies for the therapeutic application of MG53 in treatment and/or prevention of various types of muscular dystrophy. PUBLIC HEALTH RELEVANCE: Muscular dystrophies are a family of genetic disorders that all generally include progressive muscle weakness due to degeneration of the muscle fibers, which includes the most common inherited disease, Duchene Muscular dystrophy. Many of these diseases involve either fragility of the membranes that surround muscle cells or a compromised ability to reseal those membranes. Both of these cases lead to compromised integrity of the cell membrane that result in death of muscle fibers, eventual depletion of the muscle regenerative capacity, muscle fibrosis, decreased force production and in many cases death of the patient. If a therapeutic approach could address membrane fragility and reduced resealing capacity it would have efficacy across a large number of different muscular dystrophies. Current efforts within the regenerative medicine field involve examining ways to increase muscle repair in syndromes where there is a reduced regenerative capacity for the skeletal muscle. In this project, TRIM-edicine will leverage our expertise to pursue proof-of- principle studies for the therapeutic application of a novel protein, mitsugumin 53 (MG53) in treatment and/or prevention of various types of muscular dystrophy.

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