Dr. Calogera M. Simonaro, PhD

Pathogenesis and Treatment of the Mucopolysaccharidoses

Dr. Simonaro’s team is focusing on the following different aspects:

Therapies are available for some MPS disorders with limited effects in the bones and joints. Therefore, the overall goal of our research has been to use MPS animal models to study the disease mechanism in these tissues in order to develop new and improved therapeutic approaches. We have previously established that inflammation plays a major role in the pathology of MPS bones and joints, and that prevention of inflammation may have an important therapeutic effect.

Our recent generation of an MPS mouse model with an inactivated inflammatory pathway has proven that inflammation has an important role in the pathogenesis of MPS bone disease. During the past year we have also continued long-term studies using the FDA-approved anti-inflammatory drug, Remicade™, in MPS VI rats. We are hopeful that completion of the Remicade™ studies in the MPS VI rats will provide a basis for the initiation of clinical trials, and “fast-track” approval of this (and perhaps other anti-inflammatory) drugs for MPS patients.

We have succeeded at generating MPS VII/TLR-/- double mutant mice as the first “proof-of-principle” that the inflammation has a major impact on bone development. Consistent with our hypothesis and data, we have observed that inactivating TLR4 in the MPS VII animals has a remarkable effect on their growth and development. For example, inactivation of TLR4 in MPS mice led to significant increases in the length of the face and of the long bones. The double mutant MPS VII mice are much larger and have a more normal facial appearance than the MPS VII mice alone. Thus, in accordance with our hypothesis, activation of the TLR4 pathway in the MPS disorders is an important aspect of the disease pathogenesis, and inactivation of this pathway has a significant, positive effect. Continued funding will allow us to continue to examine the biochemical, pathological and clinical changes in these double mutant mice.

Based on our previous findings, we have chosen to inhibit the downstream effects of TLR4 activation using the clinically available anti-inflammmatory drug, Remicade™. This drug targets a molecule that is activated by the TLR4 pathway (i.e., TNF-a). Our results to date have shown that Remicade™ treatment can substantially reverse or prevent inflammation in the MPS VI rat model. We had previously shown that treatment of 6-month-old MPS VI rats with Remicade™ for 8 weeks reduced the levels of serum TNF-a to normal. We have now extended these findings and shown that a) in addition to TNF-a, other ?inflammatory ?molecules? also are reduced to normal in treated 6-month-old MPS VI animals, and b) inflammation can be prevented in MPS VI rats treated from 1 month of age for 24 weeks (as opposed to reversal in the 6-month-old animals). Presently, studies are underway in the MPS animals to evaluate Remicade™ treatment in conjunction with Nalgazyme™ (ERT). We are confident that these studies will support our hypothesis that anti-inflammatory therapies may be important adjuncts for the treatment of the MPS disorders.