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Director of Research ©2007 IETF Grant Application Form Please complete the following form for IETF grant applications. This form and all the attachments below must be combined into one document before submitting electronically. Grant submissions will not be accepted otherwise. Attachments Required 6SHFL¿FDLPVRIWKHSURSRVDO SDJHPD[LPXP 5DWLRQDOHRIWKHSURSRVDODQGUHOHYDQFHWRHVVHQWLDOWUHPRU SDJHVPD[LPXP 3. Preliminary data, if available should be incorporated into the Rationale/Relevance section. Preliminary data are not required for a proposal. However, if preliminary data are referred to in the proposal rationale, or have been used to formulate the hypotheses to be tested, such information must be formally presented in this section. 5HVHDUFKPHWKRGVDQGSURFHGXUHV SDJHVPD[LPXP $QWLFLSDWHGUHVXOWV KDOISDJHPD[LPXP 'HWDLOHGEXGJHWDQGMXVWL¿FDWLRQ SDJHPD[LPXP 7. Biographic sketch of principal investigator and all professional personnel participating in the project VWDQGDUG1,+IRUPDWLQFOXGLQJELRVNHWFKDQGRWKHUVXSSRUW 8. Copies of relevant abstracts and/or articles that have been published, are in press, or have been submitted for publication. &RPSOHWHGFRQÀLFWRILQWHUHVWTXHVWLRQQDLUH Cross-Sectional Study of Biomarkers for the Differential Diagnosis of Parkinson’s vs Essential Tremor Project Title: ____________________________________________________________________________ Sponsoring Institution: ____________________________________________________________________MSDx, Inc Principal Investigator: C /DVW1DPHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB)LUVW1DPHBBBBBBBBNayak RameshBBBBBBBBBBBBBB0LGGOH,QLWLDOBB 'HJUHH V BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB&XUUHQW7LWOH3RVLWPhd LRQBBBBBBBBBBBBBBBBBBBBBBBBBBBBBDirector of Research Department: _____________________________________________________________________________ Address: ________________________________________________________________________________9040 S Rita Road, Suite 1201 City: ___________________________________Tucson State: ______________________ Arizona Postal Code: _________85747 &RXQWU\BBBBBBBBBBBBBBBBBBBBBBBBBB(PDLODGGUHVVBBBBBBBBBBBUSA [email protected] 3KRQHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB)D[BBBBBBBBBBBBBB1-520-868-8716 1-888-662-9424BBBBBBBBBBBBBBBBBBBBBB All grant applicants acknowledge that the Board of Directors of the IETF is the only entity authorized to award grants on behalf of the IETF and the amounts of and occasions for awarding such grants, if any shall be awarded at all, shall be ZKROO\ZLWKLQWKHVROHDQGH[FOXVLYHGLVFUHWLRQRIVDLG%RDUGDQGLWVMXGJPHQWVKDOOEH¿QDODQGFRQFOXVLYHDQGQRWVXEMHFW to review for any reason judicial or otherwise. GrantApp5222013 32%R[_/HQH[D.DQVDV_86$_ WROOIUHH _ ORFDO _HVVHQWLDOWUHPRURUJ 2015 IEFT Grant Proposal Company: MSDx, Inc. Cross-Sectional Study of Biomarkers for the Differential Diagnosis of Parkinson’s vs Essential Tremor Specific Aims: The diagnosis of essential tremor is often misdiagnosed due to symptoms that strongly resemble those of Parkinson’s disease (PD). There are no blood tests for either Parkinson’s disease or essential tremor currently available however; a test that could differentiate essential tremor from Parkinson’s disease would be a tremendous aid to neurologists managing movement disorders. This study investigates the use of a recently developed blood test approach for diagnosing and monitoring neurological diseases with the ultimate goal of improving patient care. Thus, clinical utility is a significant driver in development of assays. Additionally, using blood samples as the basis for biomarker assays represents a technique that is cost- effective and easier on the patient and practitioner. This approach detects neurodegeneration in the substantia nigra (which is a hallmark of Parkinson’s disease). The test exploits the immune response to injury, in which macrophages are recruited from the blood to the site of injury and engulf the debris created by neurodegeneration. It has been found that these debris laden cells return to the blood stream and can be sampled and examined. In Parkinson’s disease, these macrophages contain neuromelanin. Neuromelanin is the pigment that gives the substantia nigra a characteristic black color. We would not expect to see neuromelanin in cells in the blood in essential tremor subjects as degeneration of the substantia nigra is not the cause of essential tremor. It seems likely then that this blood test could eliminate the false diagnosis of Parkinson’s disease based on clinical signs in subjects with essential tremor. This study is an important step that will provide feasibility data for seeking funding for a larger study to obtain definite data and correlate with DAT scan. Final 03.01.2015 MW/RN Rationale of this Proposal and Relevance to essential tremor The MSDx biomarker approach exploits the immune response to injury, in which macrophages are recruited from the blood to the site of injury and engulf the debris created by neurodegeneration. It has been found that these debris laden cells return to the blood stream and can be sampled and examined. MSDx discovered the presence of debris laden phagocytic cells in the peripheral blood mononuclear cells (PBMCs) of patients with multiple sclerosis (MS) and Parkinson’s disease (PD). By using antibodies to central nervous system (CNS) antigens we have revealed the presence of Tau, hippocalcin like 1, neuromelanin, UCHL1 and other proteins in PBMC lysates prepared from whole blood of MS or PD subjects. CNS antigens would not ordinarily be present in peripheral blood macrophages unless that cell had entered the brain, ingested debris and re-entered the blood circulation while carrying that cargo of CNS debris. Macrophages (phagocytic cells) are short lived in the circulation and their role is to digest ingested debris, consequently detection of CNS proteins in peripheral blood cells indicates active neurodegeneration (i.e. it’s happening now). Any type of injury is likely to trigger a response that attracts macrophages to the site of injury to clear away debris; consequently this broad approach may be applicable to many CNS diseases/injuries including the differential diagnosis of Parkinson’s Disease verses Essential Tremor if an informative selection of antigens is employed / analyzed. Figure 1 shows the results of an initial study conducted by the MSDx testing Parkinson’s disease in comparison with sex and age matched healthy controls. Eight of 10 Parkinson’s disease subjects had higher neuromelanin in blood cells than controls. What of the 2 “Parkinson’s disease” subjects with normal neuromelanin levels? Could these be misdiagnosed essential tremor patients? Additional clinical validation studies are warranted. Final 03.01.2015 MW/RN Figure 1. White VJ and Nayak RC (2015). Re-circulating Phagocytes Loaded with CNS Debris: a Potential Marker of Neurodegeneration in Parkinson’s Disease? AIMS Medical Science; 2(1): 26-34. To determine the feasibility of this blood test approach to prevent false diagnosis of Parkinson’s disease in essential tremor, we propose a cross sectional study done with blood samples from Parkinson’s disease and essential tremor subjects. The two study populations are patients recruited into the following two groups: x 10 recently (1-3 years) diagnosed Parkinson’s disease subjects x 10 diagnosed essential tremor subjects The Statement of work for the IETF Proposal (six months): 1. University of Arizona will recruit and draw the patients for this study according to a protocol that is currently in design with Dr. Scott Sherman. The finalized clinical study protocol will be submitted to the U of A IRB Review Committee for approval. 2. MSDx will receive the blood sample, process, and analyze the samples measuring neuromelanin in white blood cells according to the assay parameters outlined in the clinical study protocol. The availability of a simple and inexpensive blood test that reduces misdiagnosis of PD/ET will greatly aid the management of these diseases. Final 03.01.2015 MW/RN Research Methods and Procedure: To determine the feasibility of this blood test approach to prevent false diagnosis of Parkinson’s disease in essential tremor, we propose a cross sectional study done with blood samples from Parkinson’s disease and essential tremor subjects. Dr. Scott Sherman, the Director of the University of Arizona Movement Disorder Clinic has agreed to recruit the subjects for this study. The two study populations are patients recruited into the following two groups: x 10 recently (1-3 years) diagnosed Parkinson’s disease subjects x 10 diagnosed essential tremor subjects A fresh blood sample will be collected from each subject using one two cell preparation tube. (Becton Dickinson CPT’s with citrate anticoagulant #362760). MSDx laboratories must receive all specimens within 24-48 hours of collection. Sample Processing by MSDx-Isolation of Peripheral Blood Mononuclear cells: This procedure is common to all the work tasks. PBMC are isolated from whole blood collected in a BD Vacutainer® CPT™ Cell Preparation Tube with Sodium Citrate. The BD Vacutainer® CPT™ Cell Preparation Tube with Sodium Citrate is an evacuated Tube intended for the collection of whole blood and the separation of mononuclear cells. PBMCs are prepared according to manufacturer’s instructions. The lymphocyte and monocyte band is harvested and washed in PBS three times by centrifugation. The pelleted washed cells are then utilized for studies as detailed below. The citrated plasma is also separated from the CPT tubes for further analysis. The MSDx Assay Analysis:
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