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The dawning of molecular medicine: replacing a single defective gene

Posted on November 6th, 2009 in Health,Medicine,Science by Robert Miller

When I began my training in medical school in the 1960s, many of the drugs that would become the mainstay, front-line agents in the fight against cancer and other diseases, were just coming into play and some of them, such as methotrexate, which was initially used to treat leukemia, have remained viable drugs for treatment of cancer, psoriasis and rheumatoid arthritis. For the past 50 years or so, we have been living in what I refer to as the chemical age of medicine–in which we search for magic chemical compounds that selectively attack only one type of diseased cell or source of viral/bacterial infection, while leaving all others untouched.  In truth, this phase of medicine began during WW II, when large scale fermentation plants in the United States began producing huge quantities of penicillin from the fungus Penicillium chrysogenum, which proved, for many, to be one of the first miracle drugs available. Yet, decades later, we are still searching for the perfect miracle drug, one whose target of action is so selective that it has no side-effects or harmful untoward reactions.  The “better living through chemistry” mentality still grips contemporary  medicine, as it drives the pharmaceutical industry to search for better magic bullets in the form of improved drug design. And, over the decades, we have gotten much better at drug design because we are increasingly able to construct and visualize the three-dimensional structure of a targeted receptor or enzyme we want to modify and design a drug that will fit neatly into the critical key and lock combination leading to a desired pharmacological effect (blocking or enhancing its action). Through very special efforts, we are beginning to target specific cells with drugs by pre-selecting the cell, say a cancerous cell,  for targeted destruction using manufactured minicells that can deliver specific toxins to the wayward cells which can be identified through immunolabeling methods (It’s pretty cool and the link above goes to an article I wrote earlier on the topic).

But we know of many diseases that generally don’t lend themselves well to a magic bullet drug and among these are the hereditary diseases of which hundreds if not thousands are known today. Modern molecular biological analysis has led to the molecular identity of many hereditary diseases where the defective gene and its normal function are understood. One of the genetic disorders that commands attention is congenital blindness, a condition where children are born with defective vision and remain blind or nearly so for the rest of their life. Leber’s Congenital Amaurosis is one form of congenital blindness that may be caused by mutations in any one of 13 different genes; in about 6% of these cases, the defective gene resides in a layer of cells in back of the retina called the Retina Pigment Epithelium (RPE). The defective gene is known as RPE65; its normal mode of action is critical to maintain vision because visual pigments that have been bleached by light, and converted from a molecular configuration known as 11-cis retinal to all-trans retinal, are transported to the RPE where the enzyme “reisomerizes” the Vitamin A derivative back to the 11-cis form. The first clue to understanding these patients was a demonstration that they had very low levels of 11-cis retinal implying a defect in the regeneration of the pigment that is vital for the visual process and the defect pointed to a deficiency of the isomerase or RPE65.

The dream of every molecular biologist is to find a way to replace a defective gene and restore the health of the individual. As it turns out, a similar genetic defect to Leber’s  is found in some Golden Retriever dogs and several years ago a group at the University of Pennsylvania showed that a single injection of a modified adenovirus, that had been genetically manipulated to carry the missing gene and modified so that it would only enter RPE cells (the essence of the trick),  injected into one eye of a now famous dog named “Lancelot” resulted in a rapid restoration of his vision, which has remained normal for several years.   Two years ago, this same technique was applied to a few patients with equally good results, although the success of the procedure proved to be age-related. The longer this disease progresses without therapy, the retina undergoes a chronic degenerative change so that recovery of vision is much better the younger the patient at the time of the injection. Last month, the Lancet published a more comprehensive study of 12 patients followed for a period of up to 2 years after a single injection with ages ranging  from 8 to 44. This was the most extensive population yet tested. For each patient, the worst  of their two eyes were injected with a single application of the modified adenovirus (had to be modified over that of the dog because humans have different receptors on their RPE cells). The New York Times picked up on this story and their article provides access to a video where you can see the visual testing of a patient before and after the viral treatment.
Despite the age differences among the patients, all of them improved very dramatically with a single injection, which after two years was still sustaining and improving their visual capacity. There is some evidence that their vision continues to improve, perhaps because some learning and synaptic readjustment is taking place, though it is not clear whether this would be a brain or retina mechanism. It is fair to say that the achievements generated by the U Penn group are astounding: children normally condemned to live a life of blindness have now been given a cure by replacing their defective gene. So far only one eye of each patient has been treated and one wonders when the second untreated eye will also be injected, though one is certain that it was eventually take place.
Gene replacement therapy has now been proven in cases of Leber’s Congenital Amaurosis. The defective RPE65 gene was replaced by incorporating the normal human gene into a modified virus which was then injected underneath the retina. The virus was programmed to so that it only entered the RPE cells. In all cases, it led to dramatic improvements in vision with an average increase in visual sensitivity of 100,000 times over their pre-injection state. From the dog Lancelot to the 15 patients who have received injections so far, gene replacement has worked and patients previously condemned to blindness can now see and lead fairly normal lives. The earlier you get to the patient with this disorder, the better the outcome, though even older patients got significant improvement. The era of molecular medicine for treating blindness has begun: this is its first historic success. Now on to those patients with Leber’s Congenital Amaurosis whose defective gene is something other than RPE65! There are 12 other genes whose defects give a similar clinical picture. For them, it will take a different virus and a different gene, but with the principal established with the RPE65 patients, there is no reason to think that all patients with Leber’s Congenital Amaurosis can be effectively cured by gene replacement techniques!

This is a great moment for molecular gene replacement therapy. The achievement in treating one form of Leber’s  underscores the value of basic science research, which discovered all the key proteins, receptors and enzymes that are required for the visual pigment cycle. It was basic science that led to the concepts and tools needed to address this form of blindness and eventually all forms of hereditary diseases will be treated in a similar way. Each one of these hereditary diseases will require its own special tuning and it may not always be through an optimally tuned virus, but perhaps some other kind of vector such as a minicell. Today, science can shout from the rooftops!


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