Safety and Feasibility Study of Transvenous Limb Perfusion with Normal Saline in Human Muscular Dystrophy Due to their genetic basis and the current lack of curative therapy, the muscular dystrophies are excellent candidate diseases for gene therapies. An essential step in this development of such therapies is delivery of genetic material to a single limb to demonstrate safety and efficacy prior to systemic administration. Of the various methods of single limb delivery studied in experimental animals, high-pressure, high-volume transvenous limb perfusion shows the greatest potential to be an effective, clinically practical and generally applicable. In this project, we will perform a safety and feasibility study of transvenous single limb perfusion with normal saline in human subjects with muscular dystrophy. The study is designed as a dose-escalation safety study with the perfusion parameters increased in a stepwise manner and careful monitoring for both bcal and systemic toxicity. This design will also permit us to address the multiple logistical aspects inherent in going from animals to humans with muscular dystrophy including analgesia, vascular access and larger infusion volumes.
In Specific Aim 1, we will study young adults with limb-girdle or Becker muscular dystrophy beginning with infusions of .05 mL saline /ml of limb volume and escalating to a maximum of .40 mL/mL. An independent safety monitor will review data on each subject (perfusion parameters, laboratory and clinical testing) and must approve planned perfusion parameters for the next subject. From this study, we will determine the maximum perfusion parameters that are safe and document the degree of fluid delivery into muscle by T2 MRI.
In Specific Aim 2, we will carry out a similar dose escalation study in children with Duchenne muscular dystrophy beginning at .05 ml saline /ml of limb volume and escalating to the maximum volume determined from Specific Aim 1 as posing no greater than minimal risk. This study will provide the necessary safety and feasibility data on the perfusion technique itself to provide the basis for future regional limb delivery studies of active gene therapy. The results will be generally applicable to the single limb delivery of many different agents (oligonucleotides, plasmid-DNA and viral delivery systems) and to patients of different ages with diverse types of muscular dystrophy.
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