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Progenra Usp14 Neurodegenerative Disease Program Overview
 

Progenra Usp14 Neurodegenerative Disease Program Overview

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Over the past nine years, Progenra has developed its UbiPro™ Drug Discovery Platform for quantifying and characterizing the activity of these enzymes. This platform is amenable to high throughput ...

Over the past nine years, Progenra has developed its UbiPro™ Drug Discovery Platform for quantifying and characterizing the activity of these enzymes. This platform is amenable to high throughput screening and has been employed successfully by Progenra to identify inhibitors of both deubiquitylating enzymes and E3 ligases.

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    Progenra Usp14 Neurodegenerative Disease Program Overview Progenra Usp14 Neurodegenerative Disease Program Overview Document Transcript

    • Progenra’s USP14 ProgramTargeting the Ubiquitin Pathway for the treatment of neurodegenerative disease CONTACT: Mr. Marc Hixson Hixson@progenra.com www.progenra.comProgenra, Inc • 277 Great Valley Parkway, Malvern PA 19355 • (p) 610.644.6974 (f) 610.647.8616 • www.progenra.com Property of Progenra, Inc.
    • COMPANY SUMMARY THE UBIQUITIN PATHWAY &Progenra is a biotechnology company focused on NEURODEGENERATIVE DISEASESexploiting ubiquitin and ubiquitin-like protein pathways The ubiquitin proteasome pathway plays a multitudeto develop medicines to treat a wide range of diseases. of roles in human physiology, including neuronal proteinOver the past nine years, Progenra has developed its homeostasis. In fact, all the major chronic humanUbiPro™ Drug Discovery Platform, a suite of assays for neurodegenerative diseases are characterized by anquantifying and characterizing the activity of ubiquitin accumulation of ubiquitylated proteins in abnormalpathway enzymes. This platform is amenable to high intraneuronal inclusions. These observations support thethroughput screening and has been employed successfully hypothesis that the intracellular accumulation ofby Progenra to identify inhibitors of both deubiquitylating ubiquitylated proteins is a pathological event inenzymes and E3 ligases. Benefits of Progenra’s UbiPro™ neurodegeneration. Additional evidence of this notionDrug Discovery Program include: comes from the findings that the proteasome function is impaired in the affected brain areas of patients with AD• Identification of compounds not detectable using and PD and declines with age and oxidative stress. traditional “off-the-shelf” assays and reagents Furthermore, ~36% of cancer patients treated with the proteasome inhibitor VELCADE develop peripheral• A proven patent-pending technology for precluding neuropathy, clearly implicating proteasomal dysfunction the identification of reactive “nuisance” screening hits in neurological impairment. Therefore, therapeutic• Large panel of DUBs to be used for profiling strategies that promote degradation of the accumulated and selectivity proteins would be very relevant for the prevention and• Selective and semi-selective DUB inhibitors as treatment of neurodegenerative diseases. In addition to molecular probes proteasomal dysfunction, changes in other ubiquitin• Use of homogeneous assays that closely replicate proteasome pathway components such as E3 ligases and physiological milieux deubiquitylating enzymes (DUBs) are directly associated with neurodegenerative diseases (Table 1).• A comprehensive vs. singular approach to inhibitor identification• Best commercial platform available that covers both DUB and E3 Ligase drug discovery• Ability to instantly advance a partner’s DUB or E3 Ligase discovery program Table 1: Examples of ubiquitin pathway components involved in neurodegenerative diseases. USP= ubiquitin specific protease; UCH=Ubiquitin c-terminal hydrolase; SUMO= Small ubiquitin like modifier. Target Type Indication(s) Function Therapeutic Approach Machado- Recruit HHR23A to intranuclear Inhibit caspase cleavage Ataxin3 DUB Joseph disease, inclusions, cleaves Lys63-linkages. of Ataxin-3 Contribute to the regulation Increase activity UCH-L1 DUB PD of the pattern, activity and of UCH-L1 plasticity of synaptic connectivity. Likely involved in diseases Inhibition of USP14 results USP14 DUB caused by proteotoxic stress Inhibit proteasomes in the activation of the such as AD and ALS proteasome Degradation of CHIP E3 ligase AD misfolded proteins, slows Increase activity neurodegenerative process Parkin E3 ligase PD Neuroprotective function Increase activity Attenuates aggregation and Increase activation of SUMO Ubiquitin like AD, PD, HD proteotoxicity SUMOylation enzymes Down’s Syndrome, Progressive Forms non-cleavable, non- UBB+1 Mutant Ubiquitin supranuclear palsy, Pick’s disease, Inhibit processing degradable PolyUb chains Frontotemporal dementia, and HD Progenra, Inc • 277 Great Valley Parkway, Malvern PA 19355 • (p) 610.644.6974 (f) 610.647.8616 • www.progenra.com
    • THERAPEUTIC POTENTIAL PROGENRA’S USP14 PROGRAM OVERVIEWOF USP14 INHIBITORS While there are many neurodegenerative therapeuticThe reduced proteolytic clearance reported in target options Progenra believes that prior work andneurodegenerative diseases is exemplified by a hallmark validation of USP14 makes it an ideal target. Its technologyof Alzheimer’s disease, the presence of neurofibrillary and expertise in the ubiquitin pathway gives Progenra atangles composed of hyperphosphorylated, ubiquitylated, tremendous advantage in the identification andinsoluble, filamentous tau protein. Like many other cellular development of USP14 inhibitors for the treatment ofproteins, tau is polyubiquitylated and degraded by the neurodegenerative conditions. Screening for USP14proteasome. To facilitate the efficient recycling of ubiquitin enzymatic activity is complicated by the fact thatthree DUBs are associated with the proteasome; of these, recombinant USP14 exhibits little enzymatic activity whenUSP14 is of particular interest given its ability to deubiquitylate tested with standard DUB assay substrates such as ubiquitin-substrates prior to their degradation by the proteasome. AMC (Ub-AMC). To effectively monitor USP14 enzymaticThus, inhibition of USP14 enhances the degradation of activity, it was necessary to mix recombinant USP14 withproteasomal substrates such as tau (Figure 1) and may be purified proteasomes which had been pretreated withan effective therapeutic strategy for the treatment of irreversible DUB inhibitors to deplete their associated DUBAlzheimer’s disease and other tauopathies such as Pick’s activity. Using this strategy, Lee et al reported the firstdisease, some prion diseases, amyotrophic lateral sclerosis specific inhibitor of USP14, IU1. IU1 has an IC50 of ~5uM(ALS) and progressive supranuclear palsy. Furthermore, versus USP14 and displays selective inhibition of USP14aggregates of an additional substrate of USP14, transactive within the small panel of DUBs tested. Consistent with theresponse DNA-binding protein of 43kDa (TDP-43) have role of USP14 in deubiquitylating substrates prior tobeen reported to accumulate in subtypes of amyotrophic degradation of the proteasome, treatment of cells withlateral sclerosis and frontotemporal lobar degeneration, high concentrations (50-75uM) of IU1 enhancedincreasing the therapeutic value of USP14 inhibitors to treat proteasomal degradation of tau, TDP-43 and other proteinsneurodegenerative conditions. implicated in neuronal proteopathies. Unfortunately exploration of the chemical space surrounding IU1 did not lead to significant enhancement of the activity of IU1. In fact few analogs retain activity and these are primarily limited to substitution of fluorine with other halogens. Although IU1 has utility as a tool compound for research there is a clear need to identify and develop additional inhibitors of USP 14. Progenra has begun applying its extensive suite of technologies to initiate a drug discovery program focused on USP14. Figure 1: USP14 rescues polyubiquitylated proteins such as tau from degradation by the proteasome. A) USP14 deubiquitylates tau prior to engagement by the proteasome enabling the levels of tau protein to increase and ultimately resulting in neuronal cell death. B) In the presence of a USP14 inhibitor, polyubiquitylated tau is degraded by the proteasome resulting in a decrease in tau. A: No inhibitor No inhibitor A: B: USP14 inhibitor B: USP14 inhibitor Tau Poly Ub Tau Poly Ub USP14 AND/OR USP14 AND/OR USP14 USP14 Inhibitor Inhibitor Tau Tau 26S 26S aggregates aggregates proteasome proteasome Progenra, Inc • 277 Great Valley Parkway, Malvern PA 19355 • (p) 610.644.6974 (f) 610.647.8616 • www.progenra.com
    • PROGENRA’s USP14 INHIBITOR PROGRAM: One example of Progenra’s abilities is its identification and development of the P005091 series of USP7 inhibitors.There are several aspects of USP14 that can be exploited Progenra identified P005091 as an inhibitor of USP7 usingfor drug discovery, including catalytic activity when bound the UbiProTM Drug Discovery Platform and utilized medicinalto proteasome or subunits thereof, recruitment of USP14 to chemistry to improve potency by >10-fold while alsothe proteasome, and binding of small molecules to USP14 in improving drug-like characteristics of the compound class.the absence of the proteasome. Initial biophysical studies Progenra has demonstrated efficacy of USP7 inhibitors in ademonstrated that IU1 binds to USP14 in the absence of the variety of cell models and in multiple tumor models, andproteasome (Figure 2A), providing evidence that the can apply this experience to advance a partner’s USP14inclusion of proteasome is not necessary for the identification drug discovery program quite rapidly.of USP14 inhibitors. Progenra has applied two highthroughput screening assay formats from its UbiProTM Drug Figure 2: Initial exploration of USP14. A) SPR plot of bindingDiscovery Platform to study recombinant USP14 in the and dissociation of IU1 to USP14, but not the unrelated DUBabsence of purified proteasomes. The first assay is a non- USP47. B) Dose response analysis of the binding of USP14 tocatalytic assay that monitors the binding of a fluorescently DUBTracker™. C) Dose response analysis of USP14 activitylabeled small molecule probe, DUBTracker™, using a as measured by cleavage of Ub-luc. D)PROGRAM: Representativefluorescence polarization readout (Figure 2B). The second PROGENRA’s USP14 INHIBITOR USP14 EC50 inhibition curves aspects of USP14 thatwith the There are several as determined can be exploited for drug discovery, inassay measures the catalytic activity of USP14 in the when bound to proteasome or subunits thereof, recruitment of USP14 to the proabsence of proteasome. As stated above, USP14 has Ub-luc assay format. small molecules to USP14 in the absence of the proteasome. Initial biophysicaminimal enzymatic activity in the absence of proteasome that IU1 binds to USP14 in the absence of the proteasome (Figure 2A), prov Binding of DUB Probeand to overcome this hindrance Progenra employed A: IU1 binds USP14 B: USP14: DUBTracker™ do 40Ubiquitin-luciferin (Ub-luc) as a substrate as it is the most USP14 200sensitive DUB assay available and relies on the fact that USP47 SPR Signal (RU) Polarization, mPcleavage of ubiquitin from luciferin yields the native luciferin 20 175substrate, which then reports a luminescence signal in the 150presence of luciferase (Figures 2C, 2D). These assays 125 0enabled Progenra to monitor the function of USP14 in two PROGENRA’s USP14 INHIBITOR PROGRAM: PROGENRA’s USP14 INHIBITOR PROGRAM: 100orthogonal assays without the complex and time consuming of USP14 that can be exploited are drug discovery, including catalytic activity There are several aspects There for several aspects of USP14 that can be exploited for drug discovery, inprior preparation of DUB inactivated proteasomes. proteasome or subunits thereof, recruitment of 100to proteasome or subunits400binding of when bound to when bound 0 USP14 to200 proteasome, and the 300 thereof, recruitment -9 USP14 to the pro of -6 small molecules to USP14 in the absence of the proteasome. Initialto USP14 in studies demonstrated small molecules biophysical the absence of the proteasome. Initial biophysica Time, seconds [USP14], Log (M that IU1 binds to USP14 in the absence of the proteasome (Figure 2A), provProgenra is equally capable, however,that IU1 binds to USP14 in the absence of the proteasome (Figure 2A), providing evidence that the Binding of DUB Probe of employing a USP14 C: USP14: Ub-luc dose response to USP14 Binding of DUB Probe 1 A: IU1 USP14: DUBTracker™ dose response B: binds USP14 USP14 D: USP14: Ub-luc inhibitor p B: DUBTracker™ dovariety of HT-compatible substrates to IU1 binds USP14 activity A: monitor the 40 40 2500of USP14 in the presence of proteasome or subunits thereof USP14 200 USP14 100 200when these assays are appropriate. Additionally Progenra USP47 2000 USP47 Polarization,(RU) Polarization, mP SPR Signal (RU) SPR Signal mP 175 175can monitor the binding of USP14 to the proteasome or % Inhibition 20 20 1500 RLUproteasomal subunits using HT-compatible assays. By utilizing 150 150 50 1000a suite of assays to monitor USP14 activity and function 0 125 0 125Progenra will be able to identify USP14 inhibitorsUSP14 INHIBITOR PROGRAM: 500 PROGENRA’s with a 100 100 0variety of modes of action and explore chemical space of USP14 that can be exploited for drug discovery, including catalytic activity There are several aspects 0that is inaccessible using standard approaches. Through or subunits400 when bound to proteasome 300 0 100 200 thereof, recruitment of 100 0 -9 USP14 to200 proteasome, and binding of the -6 300 400 -9 -6 -6 1 5 5 25 25 1 03 12 0. Time, seconds Time, seconds [USP14], Log (M) small molecules to USP14 in the absence of the proteasome. Initial biophysical studies demonstrated [USP14], Log (M 0. 06 [Compound], Logthe use of its UbiPro Drug Discovery Platform, Progenrain the absence of the proteasome (Figure 2A), providing evidence that the 0. 0. TM 0. that IU1 binds to USP14 [USP14] (M)can initiate a screening campaign to identify USP14USP14 novel USP14 USP14 C: USP14: Ub-luc dose response USP14 D: USP14: Ub-luc inhibitor p C: USP14: Ub-luc dose response A: IU1 binds USP14 Figure B: USP14: exploration of doseto USP14 plot of binding and dissociation of IU 2: Binding of DUB Probe 1 response D: USP14: Ub-luc inhibitor profiling Initial DUBTracker™ USP14. A) SPR 2500inhibitors from its own or a partner’s diverse collection of 2500 40 unrelated DUB USP47. B) Dose response analysis of the binding of USP14 to DUBTra 100 PR-619 100 analysis of USP14 activity as measured by cleavage of Ub-luc. D) Representative USP1small molecules 2000 USP14 200 2000 IU1 USP47 determined with the Ub-luc assay format. SPR Signal (RU) Polarization, mP NEM % Inhibition % InhibitionHit identification using the UbiProTM Drug 20 Discovery Platform 1500 175 1500 inclusion of proteasome is not necessary for the identification of USP14 inhibitors RLU RLU 50 50is the starting point for initiation of hit-to-lead optimization. 1000 150 1000 two high throughput screening assay formats from its UbiPro TM Drug Disco recombinant USP14 in the absence of purified proteasomes. The first assay is aProgenra has identified several selective inhibitors of DUBs 125monitors the binding of a fluorescently labeled small molecule probe, D 0 500 500and utilized its expertise in this field and internal medicinal 100 fluorescence polarization readout (Figure 2B). The second assay measures 0 0 USP14 in the absence of proteasome. As stated above, USP14 has minimal echemistry to improve the potency and drug-like 0 0 absence of proteasome and to overcome this hindrance Progenra employed Ubcharacteristics of several of these small molecules. Following 300 0 100 200 400 as a substrate as it is the -6 -3 sensitive DUB assay available -6 relies on th -9 -6 most and 1 5 5 25 25 1 1 5 5 25 25 1 03 12 0. 03 12 0. 0. 06 0. 06 [Compound], Log (M) [Compound], Log 0. 0. Time, seconds ubiquitin from luciferinLog (M)the native luciferin substrate, which then reports a [USP14], yields 0. 0.initial hit identification Progenra assays a large panel 0. 0. [USP14] (M) [USP14] (M) the presence of luciferase (Figures 2C, 2D). These assays enabled Progenra to(>30) of DUBs to determine the selectivity profiledose response C: USP14: Ub-luc USP14 of initial Figure 2: Initial exploration of USP14. A) SPR plot of D:USP14 in two orthogonal profilingwithout plot not binding and dissociation of pr Figure binding and dissociation of IU1 to A) SPR but complex and time consuming IU 2:USP14: exploration of USP14. USP14, the of the Initial Ub-luc inhibitor assays USP14 unrelated hit-to-lead Dose response analysis unrelatedinactivated proteasomes.response analysis ofresponse however, of employing a vhits. This profiling is utilized throughout the DUB USP47. B) stage 2500 of the binding of USP14 toDose Progenra is equally capable, DUB USP47. B) DUBTracker™. C) Dose the binding of USP14 to DUBTra analysis of USP14 activity as measured by cleavage of Ub-luc. USP14 activity as measured by cleavage of Ub-luc. D) Representative or subu analysis of D) Representative the activity of USP14 PR-619 as substrates to monitor USP14 EC inhibition curves in the presence of proteasome USP1to ensure the development of potent, selective inhibitors. determined with the Ub-luc assay format. 2000 100 50 assays are appropriate. Additionally Progenra can monitor the binding of USP1 determined with the Ub-luc assay format. IU1 proteasomal subunits using HT-compatible assays. By utilizing a suite of assProgenra uses a combination of biophysical and function Progenra will be able NEM % Inhibition activity and USP14 inhibitors. Progenra for the identification inhibitors with a va inclusion of proteasome is not necessary to identify USP14 of USP14 inhibitorsbiochemical techniques, monitoring such high of proteasome is not necessaryformats identification ofthroughput screening assay hastoapplied its UbiProTM Drug Disco inclusion 1500 two characteristics for the RLU throughput screening assay two UbiProTM Drug Discovery Platform from itshigh 50 formats from study Progenra, Inc. 277 Great Valley Parkw ay, Malvern PA 19355 (p) 610.644.6974 (f) 610.644.8616as reversibility, binding kinetics, metabolic liabilities, and absence of purified proteasomes. The USP14 in theaabsence of purified proteasomes. The first assay is a recombinant USP14 in the 1000 recombinant first assay is non-catalytic assay that monitors the binding of a fluorescently labeled monitors the binding of a fluorescently using a small molecule probe, D labeledformulation, to characterize inhibitors further. Progenra hasreadout (Figure 2B). The small molecule measuresDUBTracker™,activity The second assay measures fluorescence polarization 500 second assay probe, fluorescence polarization readout (Figure 2B). of the catalyticextensive experience in establishing and utilizing a variety proteasome. As stated above, USP14 has minimalproteasome. As stated above, USP14 has minimal e USP14 in the absence of USP14 in the absence of enzymatic activity in the 0of cellular models for confirming the cellular activityas it DUB mostovercome this hindrance Progenra employedand tofact that cleavageassay available and relies onUb absence of proteasome and to 0 as a substrate of is the absence of proteasome Ubiquitin-luciferinthis hindrance Progenra employed sensitive DUB assay available -6 as it is on the overcome (Ub-luc) as a substrate relies the most sensitive DUB of and th -3 1 5 5 25 25 1inhibitors. In the case of USP14, Progenra will performluciferin yields the native luciferin substrate, which then reports a (M) native luciferin substrate, which then reports a ubiquitin from cellular 03 12 0. ubiquitin from luciferin yields luminescence signal in [Compound], Log the 0. 06 0. 0. 0. assays enabled luciferase to monitor2C, 2D). These Progenra (Figures the function ofassays measuring the degradation of presence [USP14] (M)(Figureswithout the complex presence oforthogonal prior preparation the DUB assays enabled Progenra pr the model luciferase of USP14 USP14 in two orthogonal assays 2C, 2D). These the USP14 in twoconsuming assays without of complex and time consuming and time tosubstrates such as tau and TDP-43. Figure 2: Initial exploration of USP14. A)isSPR plot of binding and dissociation ofaIU1 to USP14, butcapable, however, of employing a v inactivated proteasomes. Progenra equally capable, however,proteasomes. Progenra isHT-compatible inactivated of employing variety of equally not the DUB USP47. B) Dose activity of USP14 of the binding of USP14 to DUBTracker™. C) Dose response unrelatedsubstrates to monitor the response analysisin the presence of proteasome or subunits of USP14 in the presence of proteasome or subu substrates to monitor the activity thereof when these Progenra, Inc • 277 Great Valley Parkway, are appropriate. 19355 by(p) Progenra Ub-luc. (f) Representative USP14 EC50 inhibition curves monitor the binding of USP1 Malvern PA Additionally 610.644.6974 D) 610.647.8616 • www.progenra.com analysis of USP14 activity as measured • cleavage of can monitor are binding of USP14 to the proteasome or as assays assays the appropriate. Additionally Progenra can determined with the Ub-luc assay format. proteasomal subunits using HT-compatible assays. proteasomal subunits of assays to monitor assays. By utilizing a suite of ass By utilizing a suite using HT-compatible USP14 activity and function Progenra will be able to identifyactivity and function Progenra will be able to identify USP14 inhibitors with a va USP14 inhibitors with a variety of modes of action inclusion of proteasome is not necessary for the identification of USP14 inhibitors. Progenra has applied TM two high throughput Great Valley Parkw ay, Malvern PAfrom its 610.644.6974 Drug Great Valley ww .progenra.com study Progenra, Inc. 277 screening assay formats 19355 (p) UbiPro Inc. 277 Discovery Platform to PA 19355 (p) 610.644.6974 (f) 610.644.8616 Progenra, (f) 610.644.8616 w Parkw ay, Malvern
    • THE PROGENRA ADVANTAGE SELECTED PROGENRA PUBLICATIONS ANDProgenra has the singular focus of developing technologies RECOMMENDED READINGand strategies for identifying and developing selective Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartnerinhibitors of enzymes in the ubiquitin pathway for the C, Dimova N, Hanna J, Gygi SP Wilson SM, King RW, Finley D ,treatment of disease. To this end we have developed, and “Enhancement of proteasome activity by a small-moleculecontinue to develop, several proprietary and patented inhibitor of USP14.” Nature. 2010, Sep:467(7312):179-84screening technologies in addition to performing extensivebiochemical characterization of this enzyme class. Tian X, Isamiddinova NS, Peroutka RJ, Goldenberg SJ, Mattern MR, Nicholson B, Leach C. “Characterization of selective ubiquitin and ubiquitin-like protease inhibitors using a fluorescence-based multiplex assay format.”PARTNERSHIP OPPORTUNITIES Assay Drug Dev Technol. 2011 Apr;9(2):165-73.If you are interested in jumpstarting a novel drug Edelmann, MJ, Nicholson, B, Kessler, BM “Pharmacologicaldiscovery program for a validated CNS target, Progenra is targets in the ubiquitin system offer new ways of treatingan ideal partner that can bring your organization to the cancer, neurodegenerative disorders and infectiousforefront of this field. Progenra is open to discussing diseases” Expert Review Mol Med. in pressmutually beneficial licensing and risk sharing agreementsfor the screening platforms and/or the early stage Altun M, Kramer HB., Willems LI, McDermott JL, Leach CA,inhibitor leads the company has discovered. Research Goldenberg SJ, Suresh Kumar KG, Konietzny R, Fischer R,collaborations involving one or more targets are of Kogan E, Mackeen MM, McGouran J, Khoronenkova SV,high interest to Progenra. Parsons JL, Dianov GL, Nicholson B and Kessler BM.“Activity- based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes.” Chem andPARTNERING WITH PROGENRA INCLUDES: Biol. in press• Unparalleled expertise in the Ubiquitin Proteasome pathway• Access to all the tools and technology under Progenra’s UbiPro™ Drug Discovery Platform on an exclusive or non-exclusive basis to identify and develop a modifier of a deubiquitylase or ligase for use as a therapeutic• Research and early development work to assist in the identification and development of a proposed therapeutic, including counterscreening and selectivity screening• Development of new targets within the ubiquitin- proteasome pathway for the identification of modifiers of a specific ligase or isopeptidase intended for development as a therapeuticResearch collaborations with Progenra allow partners toovercome a formidable barrier to working in the ubiquitinfield, i.e., access to Progenra’s intellectual property,knowhow, and technologies. Progenra, Inc • 277 Great Valley Parkway, Malvern PA 19355 • (p) 610.644.6974 (f) 610.647.8616 • www.progenra.com