Liposome-siRNA-Peptide Complexes as Therapy to Cure Prion Diseases in Mouse Model

Summary

Principal Investigator: Mark D Zabel
Abstract: DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathies (TSEs) include scrapie in sheep;bovine spongiform encephalopathy (BSE) in cattle;chronic wasting disease (CWD) in deer and elk;and Kuru and Creutzfeldt-Jakob disease in humans. Accumulation of PrPRES, a proteinase K (PK) resistant form of the normal prion protein, PrPC appears central to the pathogenesis of these diseases. TSEs are invariably fatal diseases for which no early diagnosis or treatment exists. RNA interference (RNAi), a relatively new discovery in both plants and animals that regulates the amount of RNA available for translation into protein, has been used experimentally to limit the amount of viral, bacterial and cancer cell replication. Recent advances toward an effective therapy for prion diseases employ RNAi to suppress expression of a normal host protein, PrPC, in neurons and subsequent prion neuropathology, exploiting the phenomenon that disease severity and progression correlate with the amount of PrPC present in neurons. However, delivery of lentivirus encoding PrP short hairpin RNA for RNAi has demonstrated only modest effectiveness experimentally and limited use clinically due to the invasive delivery method, limited area and irreversibility of PrPC suppression and safety concerns. We have recently developed a novel small interfering RNA (siRNA) delivery system using liposome-siRNA-peptide complexes (LSPCs) to protect siRNAs from serum degradation, deliver siRNA specifically to neurons and knockdown PrPC sufficiently to cure prion disease in two cell culture models. Here we propose to extend this work to cure two distinct prion diseases in mice using LSPCs injected intravenously (iv) to deliver PrP siRNA across the blood-brain-barrier (BBB) to neurons throughout the brain. Our specific aims are as follows. SPECIFIC AIM 1: Determine kinetics of LSPC delivery and PrPC knockdown in mice to optimize LSPC therapy to treat prion disease SPECIFIC AIM 2: To determine whether PrP siRNA-containing LSPCs can cure established prion infection in mouse models of scrapie and chronic wasting disease (CWD) a. Infect mice with mouse-adapted strains of scrapie and CWD prions b. Monitor mice for early behavioral and cognitive defects prior to onset of clinical diseas c. Treat mice with PrP and control LSPCs using regiments varying in dosage and timing
Funding Period: 2012-03-01 - 2017-02-28
more information: NIH RePORT

Research Grants

  1. Cyclic Amplification of Prion Protein Misfolding
    Claudio Soto; Fiscal Year: 2013
  2. Conformational Conversions of Prion Protein
    Witold K Surewicz; Fiscal Year: 2013
  3. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
  4. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
  5. Role of PrPc Polybasic domains in prion conversion
    Michael B Miller; Fiscal Year: 2013
  6. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  7. Mechanisms of prion aggregation and species barriers
    Christina Sigurdson; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Cyclic Amplification of Prion Protein Misfolding
    Claudio Soto; Fiscal Year: 2013
    ....
  2. Conformational Conversions of Prion Protein
    Witold K Surewicz; Fiscal Year: 2013
    ....
  3. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  4. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  5. Role of PrPc Polybasic domains in prion conversion
    Michael B Miller; Fiscal Year: 2013
    ..Prion research also generates information about how proteins can misfold, a common event which provides an opportunity to help understand what goes wrong in Alzheimer's, Parkinson's, and other brain diseases. ..
  6. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  7. Mechanisms of prion aggregation and species barriers
    Christina Sigurdson; Fiscal Year: 2013
    ..We propose to investigate the underlying mechanisms for when and how prions can infect a new host. ..