Abuse and addiction to prescription opioids (short-acting MOP-r agonists such as oxycodone) have reached epidemic proportions in the US. Therapeutic options to block the progression of trajectory from abuse to addiction are limited. The concept of vaccination against drugs of abuse has therefore emerged for such a preventive purpose. However small molecules such as drugs of abuse are not highly immunogenic, therefore standard approaches include conjugation of the antigen epitope (e.g., oxycodone) to a protein immunogen. Effective vaccination is postulated to result in sequestration (and thus inactivation) of the drug of abuse in the bloodstream, through the action of a sufficient population of high-affinity antibodies. However, standard approaches have a number of technical limitations that can limit their reliability and effectiveness. The goal of this CEBRA proposal is therefore to develop a mechanistically novel vaccination platform based on the orderly and high-density presentation of antigen epitopes in the coat of the extracellular protozoan parasite Trypanosoma brucei (T. brucei). This biologically-evolved antigen-presentation mechanism results in strong B-cell responses and B-cell memory, crucial to effective vaccination.
Aim 1 of this multi- disciplinary proposal will therefore develop the first . brucei platform for small molecule vaccination, utilizing orderly presentation of oxycodone antigen moieties to decorate sortase "tags" transgenically expressed on the coat of T. brucei. Vaccination with inactivated T. brucei (having no potential for pathogenicity) will then be modeled in rats, and the production and time course of selective anti-oxycodone antibodies will be optimized.
Aim 2 will then focus on the "proof-of-technology" validation of this approach. This will be done through optimization of the effectiveness of anti-oxycodone vaccination in rats, monitored by pharmacokinetic (e.g., decrease in blood oxycodone levels) and pharmacodynamic (blockade of oxycodone-induced analgesia and of i.v. oxycodone self-administration) parameters. The development of this cutting-edge vaccination strategy for abused small molecules (with oxycodone as a prototype) therefore has considerable future potential for clinical translation, and for drug abuse research.

Public Health Relevance

Addiction to prescription opioids such as oxycodone (e.g., OxyContin) is associated with massive public health morbidity, and its treatment remains a challenge. The cutting-edge goal of this project is to develop a novel method to achieve selective and powerful vaccination against abused prescription opioids, based on a biologically-evolved method of antigen presentation (the coat of the protozoan T. brucei).

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA036365-01
Application #
8600481
Study Section
Special Emphasis Panel (ZDA1-SXC-E (13))
Program Officer
Chiang, Nora
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$211,875
Indirect Cost
$86,875
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065