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Biotech / Medical : VVUS: VIVUS INC. (NASDAQ) -- Ignore unavailable to you. Want to Upgrade?

To: Mkilloran who wrote (12162)	7/26/1998 7:48:00 PM
From: DaiS	Read Replies (1) \| Respond to of 23519

GENE THERAPY and ED Meathead, I have some information on the gene therapy research, carried out at the Albert Einstein College of Medicine, with which Vivus is purported to be involved and which might be of interest to you. I can give updates on this research as I learn more. I have some knowledge of genetics, but am weaker on the physiology and biochemistry, so please anyone point out errors you think I make. I need to give a basic summary of the chain of events leading to an erection. - Sexual stimulation leads to the release of nitric oxide (NO) by nerve cells into the smooth muscle cells of the corpus cavernosum of the penis. The nitric oxide is synthesised by the enzyme nitric oxide synthase. - NO then activates the enzyme guanylate cyclase. This enzyme produces increased levels of cyclic guanosine monophosphate (cGMP). - The cGMP triggers a series of events that results in the opening of potassium (K) channels (pores) in the muscle cell membrane allowing K to flow out of the muscle cells. - The movement of K out of the muscle cells results in the closing of calcium (Ca) channels in the cell membrane. This prevents calcium flowing easily into the cell. - Calcium flow is required to keep the muscle cells contracted. Without the calcium the smooth muscle relaxes and this allows blood to flow into the penis creating an erection. It appears that relaxation of the smooth muscle cells in the penis is both necessary and sufficient for an erection to occur. Alprostadil the active ingredient in muse binds directly to muscle cells and induces opening of the K channels. Adrenalin and related chemicals, that might be produced by anxiety in men suffering from psychogenic ED bind to the muscle cells and have the opposite effect, the K channels are closed and the smooth muscle contracts causing the erection to subside. Prazosin, the second ingredient in alibra counteracts such effects. Sildenafil, the active ingredient in viagra inhibits the enzyme PDE6 that is responsible for breakdown of cGMP. This results in higher levels of cGMP and more effective opening of K channels. Genes (DNA) code for enzymes/proteins. Normally for each protein we have two copies of the gene that codes for it, one inherited from our mother the other from our father. If both these copies are damaged a malfunctional protein will be produced and if the protein is important a genetic disease can result, for example cystic fibrosis. The basic idea behind gene therapy is to get cells of tissues affected by the disease to take up additional normal functional copies of the gene (cDNA) produced in the test tube. These normal copies, produce normal protein, and thus correct the defect. This same principle can be applied even when there is no genetic defect. Thus if we can get cells in the penis to take up additional copies of genes coding for important proteins, we can give a boost to the function of the cell. It is not necessary or intended that these additional copies, which may be few or many, are integrated into the chromosomes, the normal genetic complement of the cell. Rather they simply float around inside the cells producing protein and eventually are broken down in some way. However DNA is a very stable molecule, so whereas proteins or viagra or muse are eliminated from the body fairly rapidly, the cDNA can stick around in the cells for weeks or months. It should also, hopefully, be contained within the penis and not circulate round the body and cause havoc elsewhere. Looking at the mechanism of erection, the Albert Einstein team guessed that a good approach to erectile problems would be to get the smooth muscle cell K channels working well, to enhance their activity. They did this by isolating and producing in bulk in the test tube a gene (cDNA) called hSlo which codes for an important K channel protein. ((I should add that the cDNA is spliced to another piece of DNA called a vector that provides the necessary signals for the muscle cells to use the hSlo cDNA to make the K channel protein. The cDNA plus vector is called a 'construct'.)) The construct for hSlo was injected into the penis of old rats, which upon electrical stimulation showed much increased intracavernous blood pressure compared with control old rats injected only with vector. The pressure developed within the penis of the old rats was comparable with that developed in stimulated adolescent rats. They used quite large sample sizes (17 old experimental rats with 12 old control rats). Also the effect lasted for at least two months (an effect was apparent after 3-4 months but not statistically significant). They showed further, using molecular techniques, that the activity of the cDNA which they injected, and which was human in origin, could be distinguished from that of the endogenous rat hSlo gene with the penile cells of the rats. They hypothesised that the effects they observed on the penis of the rats was the result of an increase in the number of K channels in cells taking up the hSlo cDNA. So it is hoped that in humans, sexual arousal would lead to a chain of events in which higher K channel activity can be exploited to promote the smooth muscle relaxation and thus an erection. They point out that there are reasons for optimism that ED is a good candidate for gene therapy. First it appears that the muscle cells may take up the injected DNA quite efficiently compared with cells in other gene therapy projects. Second, and this is particularly important, the cells of the corpus cavernosum form a 'syncytial' network in which neighbouring cells are joined by the K channels. Thus if only a proportion of cells are directly affected by the gene therapy and take up the cDNA, the effects of this can nevertheless be transmitted to other cells through the K channels. There is another team working on gene therapy and ED that have published work. They have taken a different approach. This is to inject the cDNA coding for the enzyme nitric oxide synthase and thus boost the first step in the chain, the production of NO. They also have evidence that this is effective. However the Albert Einstein team, which appears very impressive in terms of publication record, have also tried and published on this approach and so have this covered I think. They appear to favour the K channel approach because opening of these channels is a critical proximal step for producing smooth muscle relaxation and thus an erection. As far as I can judge the unanswered scientific questions relate to precisely which cells in the penis and what proportion of cells are taking up the construct. No doubt the experiments might be repeated and the technique refined in relation to the region of injection and amount of construct injected. Clearly we can speculate about how the gene therapy might work for different types of ED sufferers and how it might be used in conjunction with other therapies. It appears that injection every few months would be needed to restore the penis to 'adolescent vigour'. Given that gene therapy is a new field, it is not obvious to me how ED sufferers would take to these periodic injections. Anyway it seems to work well in rats using a human cDNA and I would have thought that clinical trials might start fairly soon, although I do not know what legal formalities have to be satisfied. The above information is obtained from some published and some in press manuscripts. None acknowledge Vivus as the corporate address of co-authors or as providers of funds to support this research. I do not yet know when Vivus became involved and in what way. My first guess is that they might have come in fairly recently perhaps agreeing to take the work to clinical trials. DaiS