GENE THERAPY NEWS
The Keystone conference book of abstracts is now available. Here is the abstract.
Watch this SI site for more good news on gene therapy to follow after cc (if not at cc). Buy Vivus shares before it is too late. Don't miss the boat!
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Gene therapy with hSlo naked DNA preserves erectile capacity following 12-16 weeks of experimental diabetes in rats.
W.L. Smith, A. Melman, C. Santizo, Y. Sato, W. Zhao, N. Day, M. Valcic, T. Sclafani, J. Rehman, R. Bakal & G.J. Christ. Albert Einstein College of Medicine, Bronx, NY 10461.
The principles of integrative tissue physiology indicate that low efficiency gene transfer is an attractive therapeutic option for correcting peripheral organ dysfunction in systems meeting the following criteria: 1. innervation by the autonomic nervous system, 2. the primary parenchymal cell is the smooth muscle cell, and 3. the smooth muscle cells are interconnected by gap junction proteins. Under such conditions, genetic modification of only a fraction of the smooth muscle cells (i.e., #10%) would be sufficient to produce global changes in tissue function to neuronal stimulation. Consistent with this supposition, a previous publication (Christ et al., Am. J. Physiol., 1998) has documented that a single bolus intracavernous injection of naked hSlo cDNA (which encodes the a, or pore forming subunit of the large conductance calcium-sensitive maxi-K channel (KCa)) was sufficient to prevent the age-related decline in erectile capacity normally observed in older animals. That is, plasmidal transfection was sustained for at least 2 months in vivo and was associated with measurable and physiologically relevant alterations in the mean amplitude of the cavernous nerve-stimulated intracavernous pressure response (ICP); an objective index of erectile capacity. Since more than 50% of impotent men are diabetic, the goal of the current studies was to determine if KCa gene therapy would also be sufficient to prevent the decline in erectile capacity that is known to be associated with streptozotocin (STZ)-induced experimental diabetes in rats. Thus, 47 rats were made diabetic by a single subcutaneous injection of STZ (35 mg/kg). Two months after the diabetic state was established (when significant neuropathy is known to occur), all animals received a single intracorporal injection of naked pcDNA/hSlo cDNA (100 mg in 200 ml final volume). The ICP response to cavernous nerve stimulation was studied 1-2 months later, and the results are displayed below for several levels of current stimulation.
Table 1. Effects of hSlo cDNA on the mean amplitude of the ICP response following cavernous nerve stimulation.
STZ-diabetic
(N=19 rats)
Basal .06 ± .01
0.5mA .33 ± .04
2.0mA .49 ± .05
4.0mA .48 ± .04
10.0mA .45 ± .04
hSlo-transfected
(N=28 rats)
Basal .06 ± .01
0.5mA *.60 ± .04
2.0 mA *.69 ± .05
4.0 mA *.72 ± .04
10.0mA *.80 ± .04
*-significantly different from diabetic value, p<0.05 Student's t test for unpaired samples. All data are expressed as the arithmetic mean ± S.E. for the fraction of the ICP/mean arterial pressure.
These studies clearly document that KCa gene therapy can restore the STZ-induced decline in erectile capacity in rats in vivo. Such observations provide further support for the possibility that a similar genetic strategy will be useful in treating men with erectile dysfunction due to organic causes. This work was supported in part by a grant from VIVUS, Inc.
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