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  5. Medical Product Purity: Maintaining Biologics and Other FDA-regulated Products Free of the Infectious Agents of Transmissible Spongiform Encephalopathies (TSE Agents or Prions)
  1. Biologics Research Projects

Medical Product Purity: Maintaining Biologics and Other FDA-regulated Products Free of the Infectious Agents of Transmissible Spongiform Encephalopathies (TSE Agents or Prions)

Principal Investigator: David M. Asher, MD
Office / Division / Lab: OBRR / DETTD / LBTSEA

General Overview

Infections with transmissible spongiform encephalopathy agents (TSE agents or prions) cause incurable fatal brain diseases. FDA regulatory policies and product reviews reduce the chance of TSE agent contamination of products and accidental exposures. Our laboratory studies ways to detect and eliminate these infectious agents from medical products.

TSE agents have previously contaminated classes of product regulated by FDA and other US government agencies; the affected products include foods, animal feeds, animal vaccines, transplanted human tissues (cornea and brain membrane), human-derived hormones, and neurosurgical instruments; while most of those incidents took place outside the USA, more than 30 have been recognized here. In the United Kingdom (UK), TSE has contaminated products derived from donated human blood used for transfusion. These products include red blood cell concentrates that were not treated to remove white blood cells and a plasma protein called Factor VIII (antihemophilic factor), which is one of the molecules involved in blood clotting. In the UK, contaminated beef also caused fatal infections with the agent responsible for bovine spongiform encephalopathy (BSE, popularly called "mad cow" disease).

We are working to improve detection of TSE agents in various source materials used to manufacture FDA-regulated products and to develop ways to eliminate TSE agents from contaminated products. The methods we use include animal studies, in vitro studies (studies using isolated cells and extracts of tissues), and evaluation of improved methods to detect and eliminate TSE agents from both source materials (original biological materials used to make products) and finished products.

Scientific Overview

TSE agents are notoriously difficult to inactivate. The agents become exceptionally resistant to disinfection when contaminated tissues are dried on surfaces, as commonly occurs with instruments and work surfaces used to manufacture biological products and other FDA-regulated products.

Were are completing a multi-year study previously supported by NIAID, NIH, demonstrating that cell substrates used to manufacture biologics were not infected with BSE or CJD agents under simulated worst-case conditions of exposure to very large amounts of agent. Those studies are completed, except for one small collaborative effort under way in Turin, Italy. We are now studying tissues from mice and monkeys used as bioassays to confirm that they were not infected. Some remaining monkeys injected with cell cultures exposed to BSE GENT have begun to show SIGNS age-related illness but no evidence of BSE.

We have developed accessible and reproducible methods to evaluate the effects of commonly used cleaning, disinfection and sterilization methods on model TSE agents dried onto glass or steel surfaces. Our results have shown that a number of harsh methods for cleaning and disinfecting surfaces, especially combinations of pressurized steam and chemical treatments, such as lye and chlorine bleach, can remove very large amounts of TSE agents from surfaces. Nevertheless, those techniques are not fully reliable.

Although no tests have been validated as reliably detecting the small amounts of TSE agents that may occasionally contaminate source materials used to manufacture animal-derived and human-derived products, a number of promising candidate assays have been described in recent years. This project compares the performance characteristics of several recently described and older reliable tests, such as Western immunoblotting, for detecting TSE agents remaining after decontamination procedures. To date, no test has proved sufficiently sensitive and specific to screen human or animal blood or tissues (other than brain tissues) for the presence of small amounts of TSE agent. As potentially improved tests are described, the project attempts to adapt nad validate them.

During the past two years, we have adapted two sensitive new research methods that detect extremely small amounts of the abnormal form of a host "prion" protein generally found in tissues containing the infectious TSE agents. We have developed small breeding colonies of "transgenic" mice expressing or overexpressing the human prion protein to serve as sensitive bioassay animals susceptible to infection with the agent of sporadic Creutzfeldt-Jakob disease (sCJD) the most common human TSE and the one most likely to contaminate biologic products derived from human cells and tissues. We have also developed a similar breeding colony of transgenic mice susceptible to infection with the agent of BSE--the animal TSE agent deemed most likely to contaminate biologics containing manufactured with bovine-derived reagents or bovine-derived tissue devices.

(See also the Program Report of L. Gregori, PhD.)


  1. Pharmacoepidemiol Drug Saf 2020 May;29(5):575-81
    Assessment of risk of variant Creutzfeldt-Jakob disease (vCJD) from use of bovine heparin.
    Huang Y, Forshee RA, Keire D, Lee S, Gregori L, Asher DM, Bett C, Niland B, Brubaker SA, Anderson SA, Yang H
  2. PLoS One 2019 Dec 12;14(12):e0225904
    Quaking-induced conversion of prion protein on a thermal mixer accelerates detection in brains infected with transmissible spongiform encephalopathy agents.
    Kaelber N, Bett C, Asher DM, Gregori L
  3. Biotechniques 2018 Dec;65(6):331-8
    Rapid selection of single-stranded DNA aptamers binding Staphylococcus epidermidis in platelet concentrates.
    Kaur SJ, Gilman V, Duong M, Asher DM, Gregori L
  4. Arq Neuropsiquiatr 2018 Oct;76(10):705-12
    Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies.
    Piccardo P, Asher DM
  5. Handb Clin Neurol 2018;153:1-17
    Human transmissible spongiform encephalopathies: historic view.
    Asher DM, Gregori L
  6. J Gen Virol 2018 Mar;99(3):422-33
    Both murine host and inoculum modulate expression of experimental variant Creutzfeldt-Jakob disease.
    Bett C, Piccardo P1, Cervenak J, Torres JM, Asher DM, Gregori L
  7. AAPS J 2017 May;19(3):765-71
    A heparin purification process removes spiked transmissible spongiform encephalopathy agent.
    Bett C, Grgac K, Long D, Karfunkle M, Keire DA, Asher DM, Gregori L
  8. Transplantation 2017 Apr;101(4):e120-4
    Rapid testing for Creutzfeldt-Jakob disease in donors of cornea.
    Gregori L, Serer A, McDowell KL, Cervenak J, Asher DM
  9. Transfusion 2017 Apr;57(4):924-32
    Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.
    Yang H, Huang Y, Gregori L, Asher DM, Bui T, Forshee RA, Anderson SA
  10. Transfusion 2015 Feb;55(2):405-12
    Blood reference materials from macaques infected with variant Creutzfeldt-Jakob disease agent.
    McDowell KL, Nag N, Franco Z, Bu M, Piccardo P, Cervenak J, Deslys JP, Comoy E, Asher DM, Gregori L
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