143 • Vol 9 • March 2007 Gene transfer for Erectile Dysfunction and Overactive Bladder Erectile dysfunction and overactive bladder are both smooth muscle-related urogenital disorders in which altered potassium channel physiology may play a central role [1]. Potassium chan- nels modulate smooth muscle cell excitability, thereby affecting the degree of smooth muscle cell contraction and relaxation, which ultimately translates into control of hollow organ function [2]. At least four types of potassium channels are present in the plasma membranes of human smooth muscle cells [2–6]. With respect to penile erection, these ion channels respond to endogenous intracellular events by opening and allowing K + to flow down its electrochemical gradient out of the smooth muscle cell. The resulting hyperpolarization, in turn, limits calcium entry and promotes relaxation of the corporal and arterial smooth muscle cells. Similarly, detrusor overactivity is related, at least in part, to enhanced bladder detrusor smooth muscle cell con- traction (i.e., myogenic DO). Because detrusor smooth muscle contraction is dependent on transmembrane influx of calcium ions, any therapy that diminishes this process will inhibit some aspects of the aberrant detrusor contractility associated with DO. Thus, a gene transfer approach that provides the ability to locally overexpress a potassium channel gene in a target tissue could theoretically overcome the age- or disease-related changes in end-organ contractility that contribute to both overactive bladder and erectile dysfunction. In this regard, Ion Channel Innovations has thus far focused on recombinant hSlo, which encodes the α, or pore-forming subunit of the human Ca 2+ -activated K + potas- sium channel (Maxi-K). As noted above, the preclinical work leading to the ICI Erectile Dysfunction clinical trial targeted the key role played by endogenous potassium channels [7–10]. In fact, the penis is an organ uniquely suitable for gene transfer because of its anatomic and ultrastructural features. Gap junctions, key ultrastructural features of cell-to-cell communication, allow the penile corporal smooth muscle to function as a synctium, and thereby enable the use of inefficient transfer vectors, Abstract Background: Ion Channel Innovations has developed a gene transfer product, hMaxi-K, and has begun clinical trials to investigate the effect of increased expression of Maxi-K channels in the smooth muscle of the penis or bladder in patients with erectile dysfunction and those with overactive bladder. The primary function of K channels is to modulate Ca ++ infux through Ca-channels (i.e., L-type, voltage-dependent). The amount of Ca ++ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction. Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in, for example, penile erection and detrussor muscle relaxation. A phase I clinical trial that used hMaxi-K has been completed and a similar trial to assess safety of the transfer for overactive bladder is about to begin. Objectives: To assess the safety and tolerability of escalating hMaxi-K doses by clinical evaluations and laboratory tests, and to measure effcacy objectives by means of the International Index of Erectile Function scale. Methods: In the erectile dysfunction trial 11 patients with moderate to severe erectile dysfunction were given a single-dose corpus cavernosum injection of hMaxi-K, a “naked” DNA plasmid carrying the human cDNA encoding for the gene for the α, or pore-forming, subunit of the human smooth muscle Maxi-K channel, hSlo. Three patients each were given 500, 1000, and 5000 µg and two patients were given 7500 µg doses of hMaxi-K and followed for 24 weeks. Patient responses were validated by partner responses. Results: There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically signifcant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 µg and one given 7500 µg reported EF category improvements that were highly clinically signifcant and were also maintained through the 24 weeks of study. Conclusions: Effcacy conclusions cannot be drawn from results of a phase 1 trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of erectile dysfunction and other smooth muscle diseases with targeted access. IMAJ 2007;9:143–146 Plasmid-based Gene Transfer for Treatment of Erectile Dysfunction and Overactive Bladder: Results of a Phase I Trial* Arnold Melman MD 1 , Natan Bar-Chama MD 2 , Andrew McCullough MD 3 , Kelvin Davies MD 1 and George Christ MD 4 1 Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA 2 Mount Sinai School of Medicine, New York, NY, USA 3 New York University School of Medicine, New York, NY, USA 4 Wake Forest University School of Medicine, Winston-Salem, NC, USA Key words: erectile dysfunction, overactive bladder disease, smooth muscle, gene transfer, naked DNA, ion channel therapy * Presented at the 18th Israeli Medical Association World Fellowship International Conference IIEF = International Index of Erectile Function EF = erectile function DO = detrusor overactivity Original Articles