A Letter from The Office of the Vice Chancellor for Research

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OVCR Annual ReportFiscal Year 2011Technology Management & Intellectual PropertyNovel Genetic Risk Factor for Alzheimer’s Disease ProgressionResearchers at Washington University have identified a novel genetic variant that stronglycorrelates with Alzheimer’s disease progression. Dr. Alison Goate and collaborators used anestablished biomarker for the decline of AD patients (cerebrospinal fluid tau phosphorylated atthreonine 181, ptau 181 ) to find genetic variants that influence levels of ptau 181 in the cerebrospinalfluid. The study found a highly significant association between ptau 181 levels and the rs1868402SNP located within a regulatory subunit of PPP3R1 (calcineurin B), a gene previously linked toAD pathogenesis. Carriers of the rs1868402 risk allele showed a 6-fold faster rate of diseaseprogression than AD patients without the variant. Direct examination of brain samples fromAD cases and controls revealed that rs1868402is in fact associated with reduced PPP3R1 mRNAlevels and increased tangle formation, providing biological validation for the genome-wideassociation study and further implicating PPP3R1 in disease pathology. As the first geneticvariant associated with rate of AD progression to be reported, its use in clinical trial design andpatient care will translate into a significant benefit to patients. Primary Investigator: AlisonGoate, PsychiatryBlood A production and Clearance Measurements as a Diagnostic Test forAmyloidosis and Alzheimer's DiseasePrevious work from the Bateman and Holtzman labs have demonstrated clinical utility inmeasuring the synthesis and clearance rates of the amyloid-beta (Aβ) protein as a biomarker forefficacy of candidate Alzheimer’s drugs that target the protein. In a completely distinctinvention, the labs have demonstrated the ability to detect changes in Aβ in blood plasma, anassay that has utility for assessing drug candidates as well as diagnostic applications. PrimaryInvestigator: Randy Bateman, Neurology, and Dave Holtzman, NeurologyNovel Antithrombin Nanoceutical for Preventing Blood ClotsThe current invention comprises a first-in-class nanoparticulate antithrombotic that features apotent dual antithrombin/antiplatelet compound linked to a nanoparticle to function as a singleunit or drug. Advantages of this novel agent include (1) prolonged activity of drug at thenanoparticle surface and only at the site of active clotting, (2) potential for image-baseddetection and tracking of the agent and the acute thrombotic process, (3) the elimination ofharmful side effects after systemic delivery through the use of smaller drug amounts featuringsite-specific thrombin targeting and action, (4) well defined pharmacokinetics that are driven bythe nanoparticle itself and are independent of a subject’s genetics, and (5) the ability to multiplex anyother anticoagulant that is already on the market or in development for combinationtherapeutics. Studies indicate the nanoceutical outperforms standard heparin treatment, byincreasing the time to total occlusion by more than 40%. Primary Investigator: SamuelWickline, Internal Medicine, Cardiovascular Division.Novel Compounds to Treat Urinary Tract InfectionUrinary tract infections (UTI) affect a large proportion of the population and account forsignificant morbidity and high medical costs. Uropathogenic Escherichia coli (UPEC) isresponsible for up to 85% of infections and a large percentage of recurrent UTI are caused bythe same strain of bacteria as the initial UTI despite the antibiotic regimen; the current gold49
OVCR Annual ReportFiscal Year 2011Technology Management & Intellectual Propertystandard. The annual UTI incidence rate is 12.1% in women and 3% among men. Recurrencerates are high with women having a 25% to 44% chance of developing a second episode within 6months of the initial UTI. Treatment of UTI like other microbial infections is exacerbated byincreasing antimicrobial resistance and there is a huge unmet need for alternative therapies.Novel patented compounds such as Pilicides and Mannosides disrupt pili biogenesis and hostpathogeninteraction to effectively block disease progression. Primary Investigators: ScottHultgren, Molecular Microbiology and James Janetka, BiochemistryMacrocyclic Molecular BeaconsThe cyclization of fluorescent probes through bioactive molecules creates new compounds witha rigid structural framework. This agent retains the binding properties of the peptide while thephotophysical characteristics of the optical probe may be altered. The constrained conformationof the peptide conjugate modifies the selectivity of the receptor. Use of this agent can lendinsight into biological activities and facilitate the creation of disease-specific drugs. The currentinvention describes novel bioactive near infrared (NIR) macrocyclic optical compounds whosebiological and spectral properties can be enhanced through bioactive peptide-mediatedcyclization. Primary Investigator: Samuel Achilefu, RadiologyFluorescent Polymethine Cyanine DyesThe present invention provides compounds that possess a robust C-C bond containing nearinfrared chromophore as optical antenna. The C-C bond allows the development of stable dyesfor imaging and monitoring biological events such as disease-associated enzymatic activity. Thisnovel molecular design offers superior chemical stability for biomedical and analyticalapplications. Because of the biological stability, changes in spectral properties can be attributedaccurately to target biological processes such as monitoring disease-associated enzymatic activity.The C-C coupled dyes also allows for extended pi-bond conjugation, thereby enabling the use ofnew designs to obtain diagnostically useful spectral information such as pH-sensitive response insolid tumors. Primary Investigator : Samuel Achilefu, RadiologyCompounds Having Rd Targeting MotifsThe present invention provides compounds that have motifs that target the compounds to cellsthat express integrins. In particular, the compound shave peptides with one or more RD motifsconjugated to an agent selected from an imaging agent and a targeting agent. These compoundsmay be used to detect, monitor, and treat a variety of integrin-mediated biological processes,including the progression of disease states such as diabetes, cardiovascular disease, inflammationand cancer. Primary Investigator : Samuel Achilefu, Radiology50
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A Letter from The Office of the Vice Chancellor for Research

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