Onze beursstudenten

Pablo RUIZ

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Project

Evaluation of gait kinetics and lower limb muscle MRI as a practical early outcome measure of muscle function in Duchenne Muscular Dystrophy: a possible new approach to evaluate the efficacy of gene replacement therapy.

Project supervisor

Labo of hospitaal waar het project plaatsvindt

Laboratory or Hospital where the main work will be performed: Laboratory of Neurophysiology and Movements Biomechanics (Faculté des Sciences de la Motricité, ULB)

Objectives of research

The main objective is to compare the low limb joints angular moments and power generation obtained after data treatment of the locomotion movement captions recorded in a group of boys (5-8 years old) with Duchenne Muscular Dystrophy receiving a conventional DMD steroid therapy and in a group of boys of the same age, receiving the same conventional steroid therapy and also receiving a new AAV based microdystrophin gene replacement therapy (GRT) PF 0693992. This will serve to test the main hypothesis that hip kinetics will be adequate in young boys (5-8 years old) with DMD to monitor the impact of a new therapeutic drug, the AAV based microdystrophin gene replacement therapy. The secondary objective is to evaluate the correlation between hip kinetics parameters and muscle structure changes (MRI) over time in the same DMD population. This will serve to test the secondary hypothesis that quantitative MRI, looking at muscle structure, will be able to differentiate the impact of AAV based microdystrohin GRT in young boys (5-8 years old) with Duchenne Muscular Dystrophy.

Summary

Duchenne Muscular Dystrophy (DMD) is a severe genetic muscle progressive disease that affects boys and is caused by the lack of dystrophin in the muscles of patients. There is no effective curative treatment for this disease but several clinical trials aiming at replacing dystrophin in the muscle with the use of modified non replicating virus seem very promising for controlling the symptoms of the disease. Patients with DMD begin to experience changes in muscle structure that subtly affect the way they move as young as 4-5 years of age. At this time the changes are very small and hard to measure in terms of overall function (especially in these young children). Gait or walking analysis refers to the science and technology of measuring how humans move and is often used to help understand movement problems in patients with a range of different diseases. This project aims at adapting recently published techniques for measuring the forces around the joints of the legs, particularly around the hip, during walking in patients with DMD to show that measurement of such hip forces reflect early changes in muscle as a result of the disease progression and also the improvements brought about by a gene replacement therapy approach using an Adeno-associated modified virus containing “microdystrophin” gene cassette currently developed for DMD. We will also evaluate the potential stabilisation of the disease by examining the muscle replacement by fat on Muscle MRI, which is typically observed in untreated patients. We will concretely organize the secured infusion of the modified virus at HUDERF Brugmann hospital for 10 DMD patients. Afterward, we will propose these 10 patients to participate in a walk gait analysis session both at the start and end of a 1 year trial period. In parallel, we will measure gait evolution in 10 patients that did not receive gene replacement therapy. We expect to be able to measure the effect of muscle changes with an investigational drug and compare the results to MRI images that will show muscle structure changes during the trial. Finally and more generally we aim at developing a strong platform to evaluate new gene therapy approaches in children suffering from neuromuscular disorders.