Research

Helping To Find A Cure

The Isaac Foundation is pleased to report that over 97% of donations to date have gone directly towards innovative clinical research projects for MPS VI.

To date, The Isaac Foundation has given $180,000 to Dr. Calogra Simonaro and Dr. John Hopwood to help them in their quest for our common goal; a cure for MPS VI.  Lay person summaries of their research projects are below.

Thank you to all of our sponsors and donors.  With your help, we ARE making a difference.

Rescue of MPS VI pathology with small molecule chaperone therapy 

Dr. John J. Hopwood, PhD 

The Lysosomal Diseases Research Unit has identified more than 120 inherited mistakes [‘mutations’] in a protein [or ‘enzyme] called N-acetylgalactosamine-4-sulphatase (4S). This enzyme is deficient in the condition known as mucopolysaccharidosis type VI (MPS-VI). Most of these mutations lead to the formation of defective [or ‘mutant’] 4S that renders it unstable or inactive and unable to perform it usual function in the cell, which is to break down various complex materials into simpler forms for the cell to re-use. As a consequence, these materials remain ‘stored’ in cells and lead to the development of progressive clinical symptoms consistent with the disorder MPS VI.

Small compounds [or ‘molecules’], called chaperones, are able to bind to the ‘mutant’ 4S and stabilise it through the cell’s quality control machinery.  These chaperones can increase the amount of active and stable 4S that is available for the cell to use.  In previous work, we have shown that an increase in a small amount of 4S activity (for instance 5-10% of normal value) is sufficient to allow it to perform its cellular function and improve disease pathology,

We have extensively studied a naturally occurring cat model of MPS VI, and evaluated treatment for the disorder in this model. This work led to the FDA approval of a first-ever treatment for this condition, known as enzyme replacement therapy [ERT]. ERT is given to patients via intravenous infusion on either a weekly or fortnightly basis.   However, whilst ERT is effective in reducing some of the pathology associated with MPS VI [such as improving endurance, lung and heart function] it does not appear to fully benefit the bone and joint problems that are characteristic of the disorder. This is most likely because the circulating enzyme is not able to effectively reach the bone or joints because these areas do not have an adequate blood supply.

 We plan to utilise cells grown in the laboratory from the MPS VI cat to obtain proof-of-principle for the potential of chaperone therapy to treat MPS VI. Given the identification of an efficacious chaperone in cell culture we would – in a separate study - directly evaluate the efficacy of these drugs in the MPS VI cat. 

New Therapeutic Strategies for MPS VI 

Calogera M. Simonaro, PhD 

Enzyme replacement therapy (ERT) is available for three MPS disorders, but has limited effects in the bones and joints.  Therefore, the overall goal of our research is to use MPS VI and other MPS animal models to study the disease mechanism in these tissues in order to develop new and improved therapeutic approaches. 

These approaches may be used alone or as an adjunct to ERT, bone marrow transplantation or other therapies. Our research has shown that glycosaminoglycan (GAG) storage stimulates the process of inflammation in MPS bones and joints by activating a specific pathway (i.e., TLR4). 

Using funds provided by The Isaac Foundation, during the past 2 years we have demonstrated that inactivation of TLR4 in MPS mice leads to substantial improvement in their growth, including a significant increase in the length of the face and of the long bones.  This provides the first “proof-of-principle” that the inflammation has a major impact on bone development in 

MPS.  

Using The Isaac Foundation funds, we have also treated MPS VI rats with an FDA-approved anti- inflammatory drug, Remicade.  This drug targets a molecule that is activated by TLR4 (i.e., TNF-alpha).  Our results to date have shown that Remicade treatment can substantially reverse or prevent inflammation in the MPS animals.  In the current application we are proposing to extend these studies and to comprehensively characterize the bones and joints in the MPS/TLR4 knockout and Remicade-treated MPS animals (the later treated with Remicade alone or in conjunction with Nalgazyme (ERT)). 

Our underlying hypothesis is that inflammation plays a major role in the pathology of MPS bones and joints, and that prevention of inflammation will have an important therapeutic effect. 

We are also 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.