PRINCETON, N.J.—Envigo is expanding its range with new mouse models and also working toward the 3 Rs—refine, reduce, replace—to better help researchers move beyond animal testing.
Envigo announced plans to develop and internally validate five to seven ion channel in-vitro tests for measuring cardiac risk potential, ahead of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) recommendations expected at the end of 2017. These assays will form an integrated suite of tests which includes the company’s existing hERG (human ether-à-go-go-related gene) assay.
Brian Burlinson, Envigo principal scientist and vice president of safety assessment, CRS Europe, said, “There has been an exponential growth in the use of non-animal technologies in pharmaceutical and chemical safety assessment. Envigo’s goal is to be the go-to nonclinical research organization for in-vitro testing and safety development. Longer term, we are looking to internally develop new tests, and/or create them in collaboration with select partners for use across a range of pharmaceutical, agro-chemical and chemical products.”
“Envigo’s ion channel development efforts are in direct response to the long-awaited change in the guideline for cardiac ion channel assays. These were expected last year, but now it seems there will be a major review paper published at the end of this year, which will then be used as a basis for the guideline,” Burlinson tells DDNews.
From 2018 onward, Envigo expects to create between five and ten new in-vitro and in-silico tests per year. The demand for such tests is fueled by changing regulatory environments as well as technological and scientific advancements making robust in-vitro tests possible. According to Burlinson, these developments include “the ability to measure changes in the various ion channels automatically, advances in the derivation of cells (either iPPS or isolated cardiomyocytes) and the development of algorithms to interrogate data and apply things such as principal component analysis to understand any changes seen.”
The range of Envigo’s current non-animal technology assays that comply with Organisation for Economic Co-operation and Development (OECD) regulatory guidelines spans the fields of genetic toxicology, electrophysiology, metabolism, endocrine disruption, skin sensitization, skin and eye irritation, genomics and gene expression. These tests often form an essential part of integrated approaches for testing and assessment.
Envigo also announced the launch of the R2G2 mouse at the American Association for Cancer Research annual meeting in early April. The R2G2, a Rag2/IL2RG double knockout model, was created by backcrossing the common gamma chain gene mutation (IL2RG) on to a unique C57BL/6 and 129 mixed background mouse with a mutation in the recombination activating gene 2 (Rag2). The R2G2 mouse addresses common challenges researchers experience with current models used in oncology, immuno-oncology and infectious disease research.
Mike Caulfield, president of Contract Research Services and Research Model Services in North America at Envigo, commented: “R2G2 is a genetically engineered model (GEM), and its launch forms part of Envigo’s wider commitment to expand the number of GEMs in our portfolio and provide researchers with new models that address limitations with other mice currently used for research in oncology and infectious disease. Radiosensitivity testing has proven this model is less sensitive, and flow cytometry has demonstrated that the immune profile is similar to the NSGTM model. R2G2 provides a translational research approach that will help customers to more accurately predict outcomes.”
The R2G2 provides distinct advantages over other triple immunodeficient models with the SCID mutation. The model has the ability to tolerate the effects of a wider range of radiation dosages. This helps researchers more closely simulate the treatment environments of cancer therapies, where patients receive combinations of chemo/immunotherapy and radiation. The model is highly immunodeficient, due to the lack of functional T, B and NK cells resulting from the Rag2 and IL2rg gene disruptions. The R2G2 also brings the benefit of reduced “leakiness” when compared to several other models with the SCID mutations, whose immune systems regenerate as they age, forming new T cells, which can confound experiments.
In addition to the experiments already completed, Envigo is currently validating the R2G2 model’s potential humanization benefits, the outcome of which will be announced in early summer.
“Envigo wishes to partner with anyone—customers and other labs—who has a viable, relevant project which meets the following criteria: it enhances their product development opportunities or those of the industry in general; it adds to Envigo’s toolbox of in-vitro assays which we can offer to customers; and it increases Envigo’s attractiveness to (new) customers as a scientific partner,” says Burlinson.
Envigo is helping to define the non-animal technologies’ regulatory environment, with its scientists currently sitting on various OECD expert working groups. Envigo is represented on OECD local tolerance groups focused on skin and eye irritation tests, technical groups that advise on the development and revision of in-vitro test guidelines and guidance documents, as well as the International Council on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use group. Envigo has also submitted published validation data directly to the OECD and to the European Centre for the Validation of Alternative Methods, by invitation.
“Envigo’s customers use an integrated approach of in-vitro and in-vivo testing in most instances. We support those efforts, as they are required to get the most accurate results and to comply with regulatory mandates. In-vitro testing is not necessarily all about replacing in-vivo approaches, although that is one of the great benefits of it,” continues Burlinson. “Until regulations change, particularly in the pharmaceutical industry relating to the number of species and the in-vivo statistical data required to get a drug to IND, in-vivo testing will be with us for some time. We remain active in developing new in-vitro and in-vivo testing to satisfy our customers’ needs for accurate and actionable data.”
“Envigo’s main goal is to keep abreast of these [regulatory] changes and ensure we can employ these technologies to the benefits of customers while advancing the science and technology of product development testing,” concludes Burlinson. “Beyond that we have a very active ‘horizon scanning’ ethic where we look for assays that we can develop to progress Envigo’s ‘de-risking’ strategy—by this we mean the ability to offer assays which can be used early in development to investigate high-risk problem areas such as genetic toxicity, drug-drug interaction, drug-induced liver injuries, etc.”