Safety and Feasibility of High-pressure Transvenous Limb Perfusion With 0.9% Saline in Human Muscular Dystrophy

Abstract

We evaluated safety and feasibility of the transvenous limb perfusion gene delivery method in muscular dystrophy. A dose escalation study of single limb perfusion with 0.9% saline starting with 5% of limb volume was carried out in adults with muscular dystrophies under intravenous analgesia/anesthesia. Cardiac, vascular, renal, muscle, and nerve functions were monitored. A tourniquet was placed above the knee with inflated pressure of 310 mm Hg. Infusion was carried out with a clinically approved infuser via an intravenous catheter inserted in the saphenous vein with a goal infusion rate of 80 ml/minute. Infusion volume was escalated stepwise to 20% limb volume in seven subjects. No subject complained of any post procedure pain other than due to needle punctures. Safety warning boundaries were exceeded only for transient depression of limb tissue oximetry and transient elevation of muscle compartment pressures; these were not associated with nerve, muscle, or vascular damage. Muscle magnetic resonant imaging (MRI) demonstrated fluid accumulation in muscles of the perfused lower extremity. High-pressure retrograde transvenous limb perfusion with saline up to 20% of limb volume at above infusion parameters is safe and feasible in adult human muscular dystrophy. This study will serve as a basis for future gene transfer clinical trials.

Engraftment of a Galactose Receptor Footprint onto Adeno-associated Viral Capsids Improves Transduction Efficiency

“…For instance, AAV2i8G9 is a one-of-akind, chimeric strain that can potentially serve as a vector candidate for selective gene transfer to cardiac and musculoskeletal tissue through intravenous infusion. Specifically, the selective muscle tropism and ability to avoid liver sequestration makes AAV2i8G9 an optimal vector for systemic gene therapy of muscular dystrophies (33)(34)(35). We determined recently that the strain described previously, AAV2i8, yields sustained transgene expression levels in primate muscle tissue 3 .…”

Human Treg responses allow sustained recombinant adeno-associated virus–mediated transgene expression

“…AAT deficiency remains a very high target for full replacement, and many questions remain, as higher doses and immune suppression are contemplated for future trials. However, given the scalability of rAAV vector production (34), the availability of clinically tolerable limb infusion methods (22,23,35,36), and the relatively modest levels of immune suppression that may have a salient effect (6), it would seem that trials designed to achieve therapeutic levels of serum AAT should be feasible.…”

Gene Therapy in Monogenic Congenital Myopathies

“…Despite the use of high pressure, it is a safe, relatively painless option for human patients 12 and has been used successfully in animal models, including the XLMTM dogs, where there was widespread clinical improvement 2,69,70 . However, vector titers may be reduced due to the low permeability of the vascular endothelium 71 and, like direct injection, isolated locoregional perfusion does not address treatment of the cardiorespiratory system.…”