MetaboMouse®
MetaboMouse® Overview
A major aim of pharmaceutical companies is to find technologies that identify unsuitable drugs earlier, before the expense of clinical trials.
Gene Stream’s patented MetaboMouse® is one such technology.
Standard laboratory mice are commonly used in drug testing and data from these studies are used to choose the best drugs for clinical trials. However, it is well documented that many drugs, which work in mice, do not work in humans, and vice-versa. Other animal models have similar problems and this is largely related to species differences in drug metabolising proteins.
MetaboMouse® technology genetically engineers mice to be more predictive of a drug’s behaviour in humans because the genes involved in drug metabolism have been humanised to provide them with more human-like drug responses. Once fully developed, this will allow pharmaceutical companies to more accurately predict drug action, toxicity and efficacy in humans. Therefore, the best candidate drugs for clinical trials and further development can be more easily identified, and drugs likely to fail in humans are eliminated earlier before the wasteful expense of clinical trials.
The Cost of Drug Discovery and Development
DiMasi et al. (Journal of Health Economics, 2003, 22:151–185) estimated that the average cost of bringing a single drug to market is $802M (capitalised and calculated per approved drug). This represents a massive increase compared to the 1991 estimate of $318 million. The major reason for this increase is the growing cost of clinical trials, caused largely by the increasing stringency of FDA requirements for drug approval. For example, whereas pre-clinical expenses grew more than 50% from $214M in 1991 to $335M in 2003, clinical expenses grew greater than four-fold from $104M to $467M during the same period. This trend has been well recognised within the pharma industry. For example, the July/September 2003 issue of Pathways the Novartis Journal states: “Only 1 in 5000 compounds entering preclinical testing will be finally approved for use. The crucial task for industry is to find the ones likely to fail faster and earlier in the process and go on to more fruitful and promising possibilities. Since, as Dr DiMasi noted, the bulk of the costs occur at the clinical trial stage, identifying the failures pre-clinically is the goal.”
MetaboMouse® Technology
The mouse is one of the most commonly used animal models in pharmaceutical research and development. This is primarily due to their small size and rapid reproductive cycle, which allow inexpensive production and housing. Their small size also minimises the quantities of experimental drugs required for testing. Immune-deficient mice, which support the growth of human tumours, are available for testing anti-cancer drugs. Primate models are a thousand times more expensive, and ethical issues restrict their use.
In any living organism, each gene encodes a specific protein, and each of these proteins has a specific function. During evolution, different species have developed slightly different versions of the same proteins. Examples of these differences between species include the drug-binding and drug-metabolising proteins, which markedly influence responses to drugs. In the absence of a drug, the mouse and human versions of these proteins may have no other functional difference and this probably explains the particularly large species divergence of these proteins. As a result of this divergence, numerous drugs behave differently in humans compared to mice.
It is well documented that many drugs, which work in mice, do not work in humans, and vice-versa. Other animal models have similar problems. For example, a drug that works well in mice, rats or even primate models may not be suitable for use in humans if the human drug-binding proteins prevent its delivery to the target organ, or if the human drug metabolising enzymes convert that drug into a highly toxic substance. This undoubtedly contributes to the 99.98% failure rate of compounds entering pre-clinical studies.
Several proteins/genes contribute to the different action of drugs in mouse versus human. These proteins can be divided into 3 main groups;
1. Drug binding proteins that bind a drug (usually in the blood) and restrict its distribution to both the target site (thus decreasing efficacy) and other vulnerable organs (thus decreasing toxicity).
2. Drug metabolising enzymes (e.g. P450cyps and UDP glycosidase), which convert the drug into various metabolites with decreased activity or increased toxicity.
3. Drug transporting proteins (e.g. MDR1 and MRP2), which transport a drug into or out of a cell.
The levels and/or activities of these proteins often change during the course of a disease and its treatment. Therefore, in vitro simulations of the effects of these proteins are not sufficient. A whole-body model is needed. Transgenic mice that accurately mimic human drug metabolism have not been available until now.
MetaboMouse® technology uses transgenic “knock-in” methods to provide a mechanism to simultaneously remove a mouse gene from an embryonic stem (ES) cell and replace it with the equivalent human gene. The ES cell can then be isolated and used to create a line of transgenic MetaboMice that contain the genetic modification and pass it on to their progeny.
Importantly, MetaboMice, once produced, can also be sequentially crossbred with any of the existing mouse models to provide mice that express humanised drug-binding proteins and also have the desired genetic traits of any other mice.
Benefits of MetaboMouse® Technology
• MetaboMice have a more human-like drug metabolism. By testing drugs in MetaboMice, pharmaceutical companies can more accurately predict drug action, toxicity and efficacy in humans.
• Each unsuitable drug candidate identified through the properties of MetaboMouse® will save a company $millions in subsequent research costs.
• Each suitable drug candidate identified through the properties of MetaboMouse® can potentially earn $billions in total sales revenue.
Gene Stream Pty Ltd
Tel +61(0)408 903 609
