Development, Validation, and Implementation of Pharmacodynamic Biomarkers in Duchenne Muscular Dystrophy
Abstract
Duchenne muscular dystrophy (DMD) is a common and severe form of muscular dystrophy affecting 1 in 5,000 boys worldwide. The disease is caused by genetic mutations resulting in lack of expression of an essential muscle protein named dystrophin. Clinically, the disease is characterized by progressive muscle wasting, leading to loss of ambulation by 10-15 years of age and early death due to cardiorespiratory failure. Currently there is no cure for DMD, and the only treatment is corticosteroids that delay muscle inflammation for couple years but cannot cure the disease and often result in adverse side effects. Recently new and promising therapies such as those aiming to restore the missing dystrophin protein and anti-inflammatory drugs with little to no side effects are being developed. However, approval by a regulatory agency to use these new drugs as standard of care in DMD patients has been delayed due to the lack of tools to monitor drug efficacy. The only tool available today for DMD clinical trial is the 6-minute walk test, how far a patient can walk in 6 minutes. Unfortunately this test has proven to be challenging to perform by young children (4-5 years old) and also cannot be used for children who are about to lose or have lost ambulation. Therefore, the scope of children who could be tested would be limited. This renders treatment development and testing of new drugs even more challenging for this rare disease. In this research project, we propose to develop a panel of biomarkers detectable in blood circulation that are associated with DMD disease progression and, more importantly, can indicate if a drug is actually working, doing what it supposed to do or failed. Recently, we have identified several biomarkers in the serum of DMD patients. The level of these biomarkers changed with disease progression. We believe that the level of these biomarkers will also change following successful drug treatment and thus could be used to monitor efficacy in clinical trials and even as standard of care for DMD patients receiving treatment. In this project, we propose to use cutting-edge technology to measure the level of these biomarkers in blood of DMD patients before and after treatment. We will examine response of the biomarkers to two different treatments: the classical prednisone corticosteroid treatment and a new-generation drug VBP15 that acts similar to corticosteroids but with minimal to no side effects. The biomarkers that indicate if a drug is working and that can predict better outcome will be then validated in a large set of blood samples collected from ongoing DMD clinical studies. Useful biomarkers will be then proposed to regulatory agencies such as the Food and Drug Administration for qualification and approval to use in DMD drug development programs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510265
Entities
People
- Yetrib Hathout
Organizations
- United States Army