Although current animal models can represent the symptoms of PD, to date, none have been able to mimic disease onset and progression well enough to enable the development of drugs that can treat the underlying disease.
Through the MJFF grant Sigma-Aldrich’s genetic engineering unit, SAGE, plans to tackle this problem. The group will use its CompoZr zinc-finger nuclease (ZFN) knockout technology to make novel rat models that lack key genes linked to the disease.
SAGE director Edward Weinstein told Outsourcing-Pharma about the process, its advantages over other development techniques and some of the benefits the new models can provide for preclinical research.
Dr Weinstein explained that: “Genetic Engineering in the mouse has been possible for about the past 25 years due to mouse Embryonic Stem (ES) Cell technology. Try as they might, the scientific community was never really able to reproduce the same type of ES cell technology in rats, or other higher level organisms."
He added that, in contrast, his group’s technology bypasses ES cells altogether by injecting the ZFN molecules directly into rat embryos where they bind to designated target genes and induce a "knockout mutation" that prevents the correct expression of the encoded protein.
“We envision that Sage Rat knockout models will serve as better proxies for human disease conditions than currently available mouse models, which in some instances don't show the expected phenotypes.
“For instance, there are currently available mouse models of Parkinson's disease, but none effectively model the disease as well as they should, and thus don't serve as ideal proxies. Sage Rat Knockout models will serve as invaluable tools for compound efficacy screening, target validation, and safety assessment.”
The Sage group will develop five strains of rat, each with a mutation in one of the following genes: LRRK2, alpha-synuclein, DJ-1, Parkin and PINK1 and estimate that the process will take less than a year to complete.
Predicts high demand for knockout rats
The CompoZr technology, which was licensed for certain commercial applications from Sangamo BioSciences in 2007, has been used by Sage to develop a catalogue of knockout rat models for CNS and cardiovascular diseases as well as toxicology testing.
Pharmaceutical firms and contract research organisations (CRO) can buy the transgenic rodents for between $300 and $500 an animal or request the bespoke development of specific models via the SAGEspeed service.
Weinstein concluded that while rats are widely used in drug development, particularly for safety testing, now they are “amenable to gene targeting, we envision that Pharma will be among the earliest adopters of Rat Knockout technology.”
This confidence in the CompoZr technology was almost certainly a key motivation for Sigma-Aldrich's recent decision to expand its licensing deal with Sangamo, which was reported by the San Francisco Business Times yesterday.
Under the extended license agreement, Sigma-Aldrich has agreed to make a $15m upfront payment as well as an investment of $5m to buy 636,133 shares of Sangamo's common stock to maintain its rights to the technology.