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© 2011, 2012 Health Futures Digest
| Japanese researchers appear to have cured a diabetic patient by transplanting pancreatic cells from a living donor. (Cells from cadaver organs have previously been successfully used.) A less traumatic approach may be to re-engineer neurons taken from aborted fetuses and turn them into insulin-producing islet cells. Injected into normal mice, such cells produced insulin in response to an increase in glucose levels.
Gene therapy is advancing. A gene-editing process that corrects mutations in diseased human cells without introducing foreign genetic material into the chromosome could replace the gene therapy that has resulted in leukemia in some “Bubble Boy Disease” patients. Another early experimental gene therapy (involving a risky brain surgery) for Alzheimer’s patients appears to have significantly delayed deterioration in patients who have tested it for two years. The war on cancer is advancing, too. A potentially significant new approach uses “enigmols” that suppress several cancer types, without side effects. Possibly even more significant is a noninvasive RF ablation device that “has the potential to be a new modality in cancer treatment,” though details are sparse. Meantime, closer to the immediate battlefront, some biotech drugs are proving so successful in trials that the trials are being ended early, and the FDA has given fast-track designation to an experimental drug that appears to starve sarcomas to death, with few side effects. The mind-boggling potential of RNA interference (RNAi) we noted in 2003 is rapidly being realized. Australian and Japanese researchers have demonstrated the application of RNAi technology for gene replacement in plants, developing the world’s first blue (-ish) rose in the process. Such technology could prevent any viral infection in plants – and in principle, in humans. And an RNAi method of smuggling gene-silencing nanoparticles of siRNA (short interfering RNA) into tumor cells has been shown to inhibit Ewing’s sarcoma in mice. The embryonic stem cell controversy could be stopped dead in its tracks, and the exciting possibility of tissue regeneration could be started in its, if we could reverse engineer our own adult cells to become embryonic clean slates again. We can do it in mice. We can also protect mice with a genetic form of ALS from the ravages of the disease: Human neural progenitor cells re-engineered to secrete a protective protein and injected into the spinal cord succeeded in releasing their protective payload around the motor neurons the disease attacks. Human clinical trials are possible in 2006 of a similar therapy using embryonic stem cells that successfully repaired freshly damaged spinal cords in rats in 2002. Meanwhile, even patients are aware that research has moved on since 2002 and there are now possibly better approaches. (Contrast with Doctors unaware of advances in the Policy & Practice section of this issue.) If it were not for the nature of animal experimentation, Digest readers — who after all read story after story about therapeutic successes in animal experiments — might think that animals get a better deal out of medical research than humans do. And in the case of horses, they might be right. Also:
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| Cure for Diabetes
Japanese researchers have cured a diabetic patient by transplanting pancreatic cells from a living donor. Islet cells transplants using cadaver pancreases are increasingly common and quite successful in the United States, but usually require cells from at least two cadavers. On the theory that islet cells from a living donor would be more viable and therefore fewer cells would be needed, Kyoto University Hospital researchers implanted islet cells taken from half the pancreas of a 56-year-old woman into her 27-year-old insulin-dependent daughter. Twenty-two days after the surgery, the patient became insulin-independent and as of late April was still so. Islet Cells from Fetal Neurons Stanford scientists have chemically re-engineered fetal neurons (from aborted fetuses) into insulin-producing islet cells. Injected into normal mice, the cells produced insulin in response to an increase in glucose levels. The researchers plan to inject the cells into diabetic mice to see if they can reverse the disease, though the lead researcher says the cells are not yet pure islet cells — they lack proteins known to be important for islet function and development. US scientists have made a molecular repair kit that corrects mutations in a cell’s DNA. In experiments with human cells harboring mutations such as those that cause a fatal childhood disease, the new system fixed the broken genes in up to 20 percent of the tested cells — probably enough to elicit a cure if the technique were to be used on an actual patient, according to the researchers. The technique is now in animals trials, with human trials planned for next year. In contrast to conventional gene therapy — which inserts entirely new genes into patients’ cells, often inside viruses, and which has had spotty success and some fatal failures — the new method simply rewrites the small stretch of “misspelled” genetic code — it edits the human genome. With more than 4,000 diseases caused by DNA “misspellings,” the potential is big. The method has corrected (in vitro) the single gene mutation that causes “bubble boy” disease — the X-chromosome-linked severe combined immune deficiency (X-SCID) in T-cells — by treating them with custom-tailored “zinc fingers” made up of “fingers” of around 30 amino acids and a zinc atom. Each finger, depending on the combination of amino acids used, binds to a specific combination of DNA bases and is attached to a nuclease that cuts DNA. They can be designed to bind to and cut the segment of DNA containing the mutated gene, and the body itself then automatically repairs the gene where the DNA was cut. There is a possibility that some cancers are caused when broken chromosomes are rejoined incorrectly. If such problems can be overcome, the researchers hope the therapy will develop so that blood is passed through a device that will correct the genetic errors and infuse it back into the patient. They also plan to test the therapy with other genetic diseases caused by single gene mutations, including sickle cell anaemia and beta thalassemia. However, much work remains to prove the approach useful and safe. An early experimental gene therapy (involving a risky brain surgery) for Alzheimer’s patients appeared to significantly delay worsening of the disease in six patients who have tested it for two years. In one patient, the brain tissue showed new growth, Alzheimer’s destroys different types of cells in different areas of the brain; the new gene therapy targets just one of those. The preliminary success indicates that similar approaches might help other neurodegenerative diseases, such as Parkinson’s. Larger studies will begin within a year. An Alzheimer’s Association official cautioned against reading too much into such a small study. Taking a different approach, another US researcher has begun injecting the brains of up to 12 Alzheimer’s patients with an NGF (neural growth factor)-bearing virus. In animal studies, researchers from the Georgia Institute of Technology, Emory University, and Wayne State University have found that synthetic analogs of sphingolipids (cell-signaling molecules that help cells – but usually not cancer cells — decide whether to grow or die via apoptosis) called enigmols suppressed the growth of human cell lines representing cancers of the prostate, breast, colon, ovary, pancreas, brain, and blood, and reduced tumors. There were no side effects at effective doses. Enigmols are being further tested in combination with other cancer chemotherapeutic drugs. Human trials appear to be not yet in sight. Non-invasive Radiotherapy For Cancer The University of Pittsburgh Medical Center is testing in rats a noninvasive RF (radio frequency) ablation device that “has the potential to be a new modality in cancer treatment,” according to a UPMC researcher. The device uses a transmitter and receiver on each side of the rat to “focus” the radio waves, but the developer and the researchers are not disclosing how the radio waves would only target cancer cells while patent claims are in process. War on Cancer: Herceptin, Avastin Successes Genentech’s Herceptin biotech drug has been found to cut in half the risk that one type of breast cancer will recur after surgery in the 20 to 30 percent of women whose breast cancer has a particular genetic mutation that produces high levels of the HER-2 protein. Because of these powerful results, two clinical trials have been ended two years early. The chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York told the New York Times the results were “big news” because using the drug in early-stage treatment could have an impact on a greater number of women and perhaps help keep them free of cancer. Two other trials involving Genentech’s cancer drug Avastin, already approved for colon cancer, were also ended early after being shown to work for lung cancer and breast cancer as well, the Times reports. The US Food and Drug Administration has given fast-track designation to an experimental drug (designated “AP23573”) for sarcomas, the often deadly cancers that attack bone or soft tissue. The drug blocks a protein that facilitates the tumor cells’ nutrient absorption, growth, and development of blood vessels. The cells basically starve to death. The drug has an “extraordinarily low” incidence of side effects, reports the Boston Globe, but details of its effectiveness were not available at press time. An Australian biotechnology subsidiary of Japan’s Suntory has created the world’s first blue rose, using RNAi technology licensed from CSIRO (Commonwealth Scientific and Industrial Research Organization). The RNAi technology was used to switch off a gene encoding an enzyme that was blocking the researchers’ attempts to insert pansy and iris genes to make the rose blue (actually, it was mauve, but there remains only some relatively easy genetic ‘tweaking’ to produce true blue.) “The blue rose,” says a CSIRO press release, “is a harbinger of the extraordinary future of plant breeding in the 21st century.” For it opens the door to genetically re-engineering crop plants to resist any pathogenic virus, or to higher or better or different yields. A plant could be protected against several viruses by a single RNAi gene, armed with code sequences from each virus. The RNAi technique will enable crop geneticists researchers to study and understand the function of every gene, and then modify crop plants to improve yields, adapt them to saline or acid soils, or drought, or to develop plants to yield new food or industrial products, including plastics and drugs. RNAi Cancer Success In Animal Model A method of “smuggling” gene-silencing nanoparticles of siRNA (short interfering RNA) into tumor cells has been shown to inhibit Ewing’s sarcoma in mice. The “Trojan Horse” is a protein called transferrin that normally delivers iron into cells. The siRNA was engineered to target a specific growth-promoting gene active only in Ewing’s sarcoma tumors. Once inside the cancer cells, the siRNA effectively shuts down the cell’s genetic machinery, preventing further growth. In laboratory mice grafted with human Ewing’s sarcoma tumors, twice-weekly injections up to four weeks “markedly inhibited tumor growth, with little or no tumor growth in many animals,” according to one of the researchers. More research is needed before the method can be tried in humans. It is possible to reverse engineer adult cells (i.e., cells that have already “differentiated” to become a specific type of body cell) to revert to their undifferentiated embryonic state. The feat was achieved by applying a protein extract derived from newts, famous for their ability to regenerate their tails, to mouse muscle cells. The discovery could mean that mouse muscle could be given the ability to regenerate. Given that humans and mice share 99 percent of their respective genomes, we might one day be able to regenerate our own cells to treat disease or repair injury. (Another, unrelated, “baby step” toward regenerative therapy for damaged hearts has been taken with a demonstration in mice that inhibiting a protein called p38 MAP kinase allows cells to proliferate.) A Catholic priest who is also a molecular biologist told Wired he believes using the de-differentiation method to create human stem cells would eliminate the controversy surrounding the use of cells taken from human embryos and would be “an amazing discovery.” Research is now focusing on 59 DNA fragments that appear (there is much uncertainty) to enable the de-differentiation of differentiated adult cells back to their embryonic stem state in newts. Potential Stem Cell Therapy for ALS Human neural progenitor cells re-engineered to secrete a protective protein and injected into the spinal cords of rats with a genetic form of ALS (Lou Gehrig’s Disease) succeeded in finding and releasing their protective payload around the motor neurons that the disease attacks. The next step is to find out if the progenitor cells actually prolong the life of an ALS rat, and if so to conduct a phase 1 (safety) trial among a small group of patients, bypassing testing on primates. The trial would involve five ALS patients treated by neurosurgeons at the Cleveland Clinic. If it works, a similar therapy could be developed for Huntington’s, Parkinson’s, and stroke, though the lead researcher at the University of Wisconsin, where the breakthrough was made, was careful to note that a cure of the debilitating disease was still years away. Stem Cell Therapy Lets Paralyzed Rats Walk Again Human clinical trials are possible in 2006 of an embryonic stem cell (ESC) therapy that repaired freshly (but not chronically) damaged spinal cords in rats in 2002. A spinal-cord-injured patient told Wired he thought the research was “good, but . . . . It’s 3 years old, and there are other combination therapies that are showing as good or better results.” (This is a patient, mind you, not a doctor.) Potential alternatives to ESC therapy under study include the use of Schwann cells, inhibiting proteins that prevent the spinal cord from repairing itself, and the use of olfactory ensheathing cells from the mucosal lining of the nose. But ESC proponents remain “determined to pursue the research despite President Bush’s limits on federal funding of stem-cell studies,” writes Wired ‘s Kristen Philipkoski. The scientists who performed the ESC therapy on rats in 2002 more recently injected injured rats with cells derived from human ESCs and guided the cells into becoming early-stage cells critical for normal electrical signal processing in the spine. One group of rats was injected seven days after injury, another 10 months after injury. In all of them, the cells migrated to areas of the spinal cord where they were most needed, yet the rats with 10-month-old injuries failed to regain motor skills. Nevertheless, the research helped scientists further understand the processes at work, which may ultimately contribute to a therapy successful for all spinal-cord-injured patients. A California company routinely and successfully uses stem cells derived from the animal’s own fat cells to treat bowed tendons, injured ligaments, and fractures in horses. It claims the injuries heal faster and with less scarring than with traditional therapies. The company distils cells taken from a small fat sample removed from the injured horse’s rump, which are then injected at the injury site. It is not scientifically established that the stem cells are responsible for the healing, though it seems the best explanation. The company hopes to prevent injuries in horses and to treat other equine disorders, including compressive spinal cord disease and laminitis, and to treat dogs for heart disease, diabetes, liver disease, and spinal cord injuries. It is also sharing its data with several commercially related human stem-cell companies. A 3-millimetre-wide retinal chip implant developed at Stanford University could provide acuity of 20/80, enough to enable blind patients to read large forms and live independently. Light would reach the chip via a video camera mounted on goggles and a wireless, wallet-sized computer. The computer processes the video and sends it to an infrared LED screen on the goggles, which then reflects an infrared image into the eye and on to the retinal chip, where photodiodes convert the light into electrical signals and send them on to the brain. The goggles are transparent so if the user still has some vision, they can match that with the new information. Blind rats fitted with the chip passed a vision test by responding to having a pattern of black and white stripes waved in front of them. Much work remains before human trials can be contemplated. A harmless bacterium that binds to the HIV virus has been discovered by researchers at the University of Illinois at Chicago’s dentistry college. A strain of lactobacillus binds to the mannose (a sugar) envelope on the surface of HIV, since the sugar is a food source to the bacterium. With colleagues at Rush University, the researchers isolated the lactobacilli from the oral and vaginal cavities of healthy human volunteers, then tested them against HIV and found two strains that specifically trap the virus by eating mannose and — in the lab at least — block infection. The researchers are planning to conduct clinical trials. Unlike an AIDS vaccine (which remains an elusive goal), an HIV-capturing lactobacillus would be safe, simple, and provide protect against all subtypes of HIV. It could protect infants against HIV in breast milk and, by inoculating the mucosal surfaces where HIV transmission occurs, it could protect women against sexual transmission of the virus. It would also be much less costly – “a few millions” of US dollars – to develop than the $100 million to $1 billion costs to develop a single vaccine. Scientists at the Fred Hutchinson Cancer Research Center have succeeded in making mice hibernate, and then wake up, on demand. The method was simply to add 80 parts per million of hydrogen sulfide to the air in a chamber. Upon re-exposure to normal room air, the mice quickly regained normal function and metabolic activity with no long-term negative effects. During hibernation, cellular activity slows to a near standstill, drastically reducing the need for oxygen. The hope is to be able to induce hibernation in critically ill human patients with ischemic ailments including severe blood-loss injury, hypothermia, malignant fever, cardiac arrest, and stroke. The researchers also hypothesize that cancer patients placed in hibernation could tolerate higher radiation doses without damaging healthy tissue, since cancer cells — not dependent on oxygen to grow — are more resistant to radiation than surrounding healthy cells. Temporarily eliminating oxygen dependence in healthy cells could make them a less-vulnerable target for radiation and chemotherapy and thus spare normal tissue during high-dose cancer therapy. Hibernation might also extend the amount of time that organs and tissues could be preserved outside the body prior to transplantation, and accelerate wound healing in patients whose ability to do so is compromised. Humans have been known to enter prolonged hibernation-like states with no lingering physical or neurological damage, including a Norwegian woman who was resuscitated after being submersed in icy water for more than an hour and a Canadian infant who wandered outside in a nightdress one wintry night and was resuscitated two hours after her heart had stopped beating. The researchers believe induced hibernation could change the way medicine is practiced by being able to buy patients time. Time is of the essence to patients arriving at the ER with severe fevers of unknown origin, who are at risk of brain-damaging seizures during the time it takes to diagnose the bacterial or viral cause and administer the proper antibiotic. The researchers believe they now know how to stop such a fever “on a dime.” UCLA researchers have found a natural molecule that can be used to heal fractures and generate new bone growth. The discovery could lead to faster and more reliable bone healing, with fewer side effects than another protein (BMP) currently used in bone repair, and at a lower cost. It could be used to repair cleft palates and in spinal fusion and implant integration. The researchers have formed a company to commercialize the product, for which they anticipate FDA approval and first sales within the next seven to nine years. University of Texas researchers have discovered that the peptide T59 will attach to a synthetic, non-toxic, conductive plastic called polypyrrole, giving the plastic the ability to attach to cells. A possible application of the discovery would be in stimulating nerve growth by wrapping the plastic around damaged nerve cell extensions called neurites, then applying an electric field and perhaps adding growth factors to help them regenerate. The researchers plan to study T59 as a linker to other molecules in the future, possibly including vascular endothelial growth factor, which stimulates the growth of new blood vessels. A software program under development at Posit Science Corp. is claimed to help prevent and even reverse memory loss, declining vision and hearing, reduced motor control, and other symptoms of aging, reports the San Francisco Chronicle. The “Brain Health Training Program” has various modules that total about 40 hours, designed to be completed over about eight weeks. Posit Science says the program is based on rigorous scientific research, some of it conducted by the company co-founder and Chief Scientific Officer, a professor of neuroscience at UCSF. The program’s “cognitive calisthenics” are progressively more difficult videogame exercises designed to stimulate specific brain functions. The first module, focused on hearing, is expected to be on the market by the end of the year. Future modules will address eyesight, problem solving and multitasking, motor control, and balance and mobility. Pricing will vary from less than $50 to $1,000 depending on intensity levels and other factors, and may be site-licensed to nursing homes. The company says studies on 40 test participants with mild cognitive impairment enrolled through UC Davis Medical School’s Alzheimer’s Disease Center have shown their memory improving as if they were 10 years younger, and hearing has become sharper in some. Twenty of them use the software. The other 20 spend the same time doing self-selected computer activities. MRIs, PET scans, and neuropsychological testing are conducted before and after the six-week trial, but as of press time it appears there was not yet enough data to assess whether the software works as promised. |
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