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Accepting the risk in hopes of a cure 2 area Parkinson's patients take part in Ceregene's experimental treatment By Penni Crabtree UNION-TRIBUNE STAFF WRITER December 8, 2006 SCOTT LINNETT / Union-Tribune David Kruest underwent an experimental gene therapy this year to treat his Parkinson's disease. He believes his symptoms have improved since the treatment. In the dry language of clinical trial records, they are known as Patient 2 and Patient 12. But the quest by Vista chiropractor Brad Arens and San Diego real estate broker David Kruest to find some relief from Parkinson's disease, a chronic, degenerative central nervous system disorder that can leave sufferers with little or no mobility, is anything but prosaic. It's a tale of a cutting-edge experimental therapy in a field fraught with medical disasters. Of a profit-motivated biotechnology company that managed to tap into a nonprofit cash stream with Hollywood cachet. And of desperate patients who suddenly find themselves pioneers, helping to push forward the scientific frontier. Along the way, Arens and Kruest got a rare glimpse of how risky science moves forward despite the brutal financial climate for early-stage drug companies, and how self-interest and altruism can sometimes find common ground in the search for medical cures. For Kruest, who this year became the last of 12 patients to undergo brain surgery to implant an experimental gene therapy developed by San Diego's Ceregene, the quest began 13 years ago while driving his car to work. Glancing down, Kruest watched with foreboding as his hand scuttled like a spider across the seat. "It walked across the seat of its own power, like it had a life of its own," Kruest, 59, recalled. "I looked at it and thought 'what the heck is this about?' " Brad Arens of Vista practiced yoga in his living room as part of an exercise regimen to battle effects of Parkinson's disease. It turned out, after an initial misdiagnosis, to be Parkinson's disease, a disorder that occurs when nerve cells, or neurons, in a part of the brain called the substantia nigra lose their ability to produce dopamine, a crucial chemical messenger. When that happens, the neurons in the brain fire erratically, affecting control of limbs and speech. Though the disease progresses differently with each patient, problems such as tremors, muscle rigidity, shuffling gait, blurred speech, mood disturbances and memory loss take hold. "When I found out that I had a neurological disease that was degenerative and incurable, I tried to forget about it. Not deny it, but not give it any power," Kruest said. "But it was always there, always present. I was always hurting. I tried to keep on moving, but I kept on moving slower." Over the years, Kruest tried various medications and enrolled in a clinical trial to gain access to one experimental drug, which was eventually approved for use in the United States. But every therapy was "cosmetic," helping to relieve symptoms but not slow or halt the progress of the disease, Kruest said. Then, last December, Kruest read about a fellow San Diegan who was among the first to undergo Ceregene's experimental gene therapy, and Kruest decided to track him down. Arens, 53, wasn't surprised to get the call. Ever since his name appeared in a media account of the therapy, numerous people with Parkinson's disease had contacted him, seeking information. Arens' battle with Parkinson's disease began in the fall of 2001, when he began having trouble with his coordination. While helping out with his childrens' school, another parent, a sharp-eyed nurse, observed his fumbling and suggested that he look into the possibility of Parkinson's disease. The nurse proved to be correct, and Arens searched the Internet and consulted experts seeking options. "The pathway of this disease is not a pretty picture, so I was trying to do everything I could to interrupt its progression," Arens said. Ultimately, Arens hit on the Ceregene therapy after failing to qualify for another study. "For me it became a risk-benefit ratio, and I came to the decision it was the best thing for me," said Arens, who believes his gait and coordination have greatly improved. "I still think it is the best thing for Parkinson's. Compared to everything else out there, this is the hottest ticket in town." Kruest quizzed Arens about the procedure, and what he learned initially gave him pause. The treatment required surgeons to drill a small hole in his skull and inject, in a specific portion of the brain, a viral shell that carried a gene that codes for a protein called neurturin. Once in the brain, certain cells take up the gene, which tells the cells to start making the potent nervous system growth factor. In animal studies, neurturin has been shown to not only protect brain cells afflicted by a Parkinson's-like disorder, but to ease symptoms and repair some of the damage. But something that looks promising in animal studies can turn out to be a big stretch for humans, as the field of gene therapy has proved in the past. The well-publicized death in 1999 of Jesse Gelsinger, a teenager who died during a gene therapy experiment at the University of Pennsylvania, was a huge setback for the field. For a time, that failure and others halted clinical trials, dried up funding and led to the demise of several gene therapy companies. Ceregene was founded in January 2001, soon after the peak of the biotechnology boom. But unlike the genomic start-ups that captured the imagination of investors at the time, the tiny biotech was never going to have an easy path. Yet a year earlier, the popular actor Michael J. Fox announced his retirement from the ABC television show "Spin City" and the establishment of the Michael J. Fox Foundation for Parkinson's Research. Fox had publicly disclosed earlier that he had been diagnosed with Parkinson's disease, and he dedicated his foundation to finding a cure for the disorder within a decade. For cash-strapped Ceregene, which is also developing gene therapies for Alzheimer's disease and Huntington's disease, it was a match made in heaven. With a tight budget, clinical studies often have to be "cut to the bare bones" of what is essential for product development, said Raymond Bartus, Ceregene chief operating officer. Last year, the foundation gave a $740,000 grant to Ceregene to help fund the Phase 1 clinical trial. Bartus said the grant allowed the company to enhance the depth of the scientific data, including funding special brain scans to help measure whether biological changes occurred. For Kruest, the fact that the foundation found Ceregene's work worthy of funding also helped assuage some concerns. "I was very scared: They were going to open you up, do some injections and seal you up," Kruest said with a rueful laugh. "It was like these guys were going to have a party in my head, and I'm not invited." Encouraged by Arens experience and his own research, Kruest decided to become Patient 12, the last to be treated in the pilot study at the University of California San Francisco. In October, the results were presented at a scientific meeting in Chicago. The Ceregene therapy appeared to reduce symptoms of Parkinson's disease by 40 percent, and the patients - all of whom were advanced in their disease and couldn't control it with standard medicines - reported a doubling of good quality 'on' time, when they felt they were functioning well, according to self-reported diaries. Based on those results, the Fox foundation decided to chip in an additional $1.9 million to fund a larger Phase 2 clinical study that will test the treatment in 50 volunteers. Dr. William Marks, UCSF associate professor of neurology and principal investigator for the study, said the Phase 1 results should be viewed with caution. The small size of the study, and the lack of a nontreated "control" group to compare results against, makes it impossible to draw definitive conclusions. "One needs to strike a balance between scientific excitement at what this approach could bring, and the need to prove it first," said Marks, who will lead the planned Phase 2 study, which will be placebo-controlled. "But whether it ends up working or not, we are entering a new medical era," Marks said. "Just the fact that we can explore these options is very exciting for the medical community and our patients." Marks commended the collaborative effort between Ceregene and the Fox foundation, and praised the patients who took part in the groundbreaking study. "It takes a special sort of person to move forward with an experimental treatment before it has been proven," Marks said. "These two people have provided important information that will allow another 50 people to be involved in this. "Sure, they want to get better themselves, but they also want to contribute to the welfare of others," Marks said. "I think it is important to know there is hope out there, innovative stuff going on, and these people help give that hope." Kruest, who is now pursuing activities like swimming that he couldn't do before, said he wants to figure out what to do with the rest of his life. It's an exercise he thought he had abandoned. "Before, there was no tomorrow, it was a degenerative disease that can kill you," said Kruest. "Today, there is a tomorrow. I can see that." ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn