Pharmacology/Toxicology Core

PHARMACOLOGY/TOXICOLOGY CORE Lovelace Biomedical and Environmental Research Institute Lovelace Resporatory Research Institute Albuquerque, NM P I: Janet M. Benson, P h D, D A B T

Introduction:

The Pharmacology/Toxicology Core is a comprehensive research facility conducting IND-enabling safety and biodistribution evaluations of potential new gene therapies for the NHLBI’s Gene Therapy Resource Program. Results of the gene vector testing will support development of human clinical trials. The pharmacology and biodistribution studies assess vector tropism, gene expression efficiency and kinetics, and vector clearance. The safety studies identify any potential adverse effects of the vector or transgene product.

Types of Services:

Assist Investigators in development of Request for Services Applications to the GTRP

  • Initial Consulting on Study Design, Input into INTERACT and pre-IND Packages to FDA.
  • Participate in meetings with FDA and assist responding to FDA questions regarding experimental design.

Product Delivery Methodologies – Lovelace has a toxicology and excellent veterinary staff enabling vector delivery by traditional and less traditional methods

Examples of product delivery routes used:

  • Intravenous
  • Intramuscular
  • Intraplueral
  • Intrathecal
  • Intra-ocular
  • Intra-articular (knee joint)
  • Open chest epicardial painting

Animal Species Available for Toxicology or Biodistribution Studies

  • Rodents (mice, rats, guinea pigs, hamsters)
  • Rabbits
  • Ferrets
  • Dogs
  • Non-human primates
  • Swine
  • Specific animal models can be purchased or developed as needed

In Life and Post Life Data base

Body weights, detailed clinical signs, gross pathology and histopathology findings are documented in the Provantis Data Base (Instem).

Vector/Gene Product Analyses

  • Real time PCR for analysis of viral vector load
  • Reverse transcriptase PCR (gene expresssion)
  • Western blot
  • Cytokine analysis (ELISA and Luminex)
  • Immunohistochemistry

Necropsy, Histopathology, and Pathology Capabilities

  • Necropsy facilities for large and small animals
  • In House histopathology laboratory – traditional and "special stain" capabilities
  • Board certified pathologists

Clinical Pathology Laboratory

  • In house capabilities for hematology, serum chemistry, and coagulation parameters
  • Special analyses can be developed and validated as needed
  • Historical data base for rodents, dogs, swine and non-human primates

Quality Assurance/Regulatory Oversight

  • Protocols, amendments, study specific procedures and critical phases of studies are audited by the Quality Assurance.
  • Final reports are audited against the study files.
  • Study records are archived on site.

FAQs

Who can apply for these GTRP resources?

For all types of RSAs for laboratory services

  • The scientific research in gene therapy that is the subject of the RSA must be consistent with the NHLBI Mission (https://www.nhlbi.nih.gov/about/strategic-vision) or, if the research addresses a disease area consistent with the mission of another NIH Institute, that Institute must agree to cover the cost of the service.
  • The investigator must complete the on-line Registration Form on the GTRP main web page and receive approval by the NHLBI Gene Therapy Group (GTG) allowing the investigator to submit an RSA.
  • RSA approval and implementation is contingent upon availability of funds in the GTRP.
  • Services provided through an approved RSA are at no cost to the investigator.
  • The various types of RSAs are independent of one another. An applicant Investigator may submit any type of RSA for a qualified gene therapy research project regardless of past or future utilization of GTRP resources for the project.

In addition, for Pharmacology/Toxicology Studies

  • The applicant must provide documentation of a pre-IND FDA meeting/review and FDA-specified pharmacology/toxicology testing recommendations.
  • A brief description of the anticipated gene therapy clinical trial must be provided by the applicant.

What is the mechanism for obtaining these GTRP resources?

A Request for Service Application (RSA) is the mechanism for applying for GTRP resources. Investigators must register on-line and be approved by the NHLBI Gene Therapy Group in order to access the Request for Service Application.

What type of information will the approved applicant investigator need to provide to the laboratory on the Request for Service Application?

In order for the laboratory to adequately test the gene vector product, the applicant investigator will be asked to provide such information as:

  • background data on vector construct (plasmid map including restriction sites; packaging cell lines, serotype,etc)
  • sequencing data of vector expression cassette
  • method of assessing gene transfer and efficacy
  • animal model requirements; dosing and schedule

The applicant investigator is encouraged to contact the laboratory for assistance in completing the RSA.

About the Biomedical and Environmental Research Institute

Lovelace Biomedical and Environmental Research Institute is a subsidiary of the Lovelace Respiratory Research Institute. The Institute has a long history of conducting toxicology studies on a wide spectrum of agents (including inhaled gene products) in a variety of animal species. Lovelace has served as the Pharm/Toxicology Core of the NHLBI Gene Therapy Resources Program for GTRP1 and GTRP2 (10 years). The pre-clinical toxicology and pharmacology studies are conducted under FDA Good Laboratory Practice Guidelines (21CFR Part 58) to support IND submissions.