1st Year Research Reviews – 2010

MPS II
Brett E. Crawford, Ph.D.
Zacharon Pharmaceuticals Inc., La Jolla CA,
Glycosaminoglycan inhibitors as substrate reduction therapies for MPS II”

With the support from the National MPS Society, we have made significant progress toward developing a new therapeutic approach designed to treat both the neurological and non‐neurological symptoms of MPS.  This approach is based on chemical compounds that modify glycosaminoglycan synthesis so that certain lysosomal enzymes are not required to degrade them.  The following is a brief description of our progress over the last year:

Improve the Potency of the Lead Compounds. The first goal of our proposed research is to improve the potency of the inhibitors to a level needed for robust efficacy in experimental models and in patients.  This is a very important stage in drug development to ensure that the drug can be administered at effective doses and is sufficiently selective to be safely used in humans.  Using the cellular assay of MPS that we developed though our previous MPS Society funding, we have successfully increased the potency of the compound by over 100-fold.

Identify Safe and Effective Drug Candidates. With significant progress on the potency, we are now focused on improving other drug like properties required for clinical development.  These features include the selectivity, pharmacokinetics, stability, and formulation.  Through these studies we aim to identify a potent analog that has all of the characteristics in a drug candidate that is suitable for clinical studies in MPS patients.

Through the next year of support, we are excited to test these optimized compounds in the mouse models of MPS.  Due to the broad efficacy of this therapeutic approach we expect to test these compounds in models of MPS I, II, and III.

Partnership for Further Development. Based on the progress that we have made through MPS Society grants, NIH grants, and private investors, we are also happy to report that we have entered into a strategic research collaboration with Pfizer to jointly develop these compounds as novel therapeutics for the treatment of MPS.