Grant: Proof of Principle Program - Phase I

The vast majority of therapeutic drugs that have been used to treat illnesses over the past one hundred years and more have been small molecules. These typically inhibit specific enzymes or block particular receptors to have a therapeutic effect. Another class of therapeutic drug that is rapidly increasing in importance is that of therapeutic proteins, which already represent 50% of the drugs in development. These often replace the function of human proteins that are deficient in the patient, or block processes that are damaging. Most of the therapeutic proteins used or in development have specific sugars attached to their surfaces that play important roles in directing these drugs to their target in the body, and in keeping the drugs circulating in the blood stream. Possibly the most important of these sugars, typically "capping" the end of the sugar chain to protect it, is sialic acid. When sialic acid is removed from the surface of the protein by enzymes in the blood then the protein is cleared from circulation. The faster a therapeutic protein is cleared, the more often it needs to be replaced, meaning patients need treatment more often or with higher doses. This greatly increases the cost and discomfort of treatment. Our laboratory has discovered and patented a simple way to slightly change the structure of sialic acid such that its removal from sugar chains by enzymes is slowed enormously. In this project we shall develop ways to attach these modified sialic acids to proteins and explore whether their incorporation in place of the normal sialic acid will slow down the degradation of these proteins, to increase the time they spend in circulation. If this is successful then the dosages of these therapeutic proteins can be lowered considerably and they can be given much less often to patients. Not only would this result in very substantial savings for our health care system but also the less frequent dosages would improve the quality of life for patients.