RNA interference (RNAi), we noted in December 2003, offered remarkable promise. Now, for the first time in a live animal, a “simple” RNAi therapy has essentially cured mice of a disease similar to Huntington’s, and it could work against Alzheimer’s, too. If it can be successfully applied to humans, RNAi therapy will represent a revolution in medicine.

Iceland’s visionary and ambitious population genome project is leading to the production of pharmacogenomic drugs in a manner more effective and efficient than traditional drug discovery, and could mark the beginning of a major trend.

“It’s finally getting to the exciting point,” a researcher said of developments in the war on cancer. His excitement stems from a whole new understanding of cancer, based on new evidence of the existence of cancer stem cells relatively impervious to standard therapies. Adding to the excitement are: a device using electroporation (electronic pulse technology) for opening up cancer cells to large-molecule drugs, now on the FDA”s fast-track approval process, that could eliminate cancer surgeries, along with their high costs, risks, and uncertainties; and a marijuana extract that could one day form the basis of some cancer treatments, since new findings show that cannabis extracts have an anti-angiogenic effect, shrinking brain tumors by blocking the growth of blood vessels that nourish them.

A cancer drug we reported in May as being effective but having side effects has had the side effects drastically reduced without affecting its potency.

Other exciting events in therapeutics:

• A partially paralyzed American has recovered sensation and movement after receiving a glia cell transplant from aborted fetuses in China.
• German surgeons have successfully transplanted a new jawbone grown in the patient’s back muscle into the patient’s mouth. The surgeons themselves are not sure why it worked, but stem cells may have played the key role.
• Biomolecular engineering could achieve a blockbuster success in ridding the world of malaria, if recently-begun clinical trials succeed.
• An exoskeleton to enable the disabled to walk could make its commercial debut later this year, though as with all such advanced products, the timing could be off by a considerable margin.
• We first wrote about the VeriChip implantable ID chip in September 2003. Now, the FDA may be about to give it a boost, by allowing its use to identify hospital patients. On the other hand, the FDA has rejected the use of a depression “pacemaker” device (as well as the agency’s own experts’ advice” again.)
• A recently FDA-approved ultrasound drug injector spells the beginning of the end for needles in medicine. It will eventually render the virtual hand described in the Devices section redundant, at least as a tool for teaching nurses in administering injections.
• Tissue regeneration from stem cells will likely be here by 2020 if not sooner, given NASA”s need for a backup plan should efforts to prevent radiation damage to Mars mission astronauts fail.
• An implantable RVAD (right ventricular assist device) under development could, coupled with an available implantable LVAD, substitute for a heart transplant.
• An artificial retina could be in clinical trials as a permanent prosthesis by 2006.
• Telepsychiatry conducted via videoconferenceis as effective as, and no more expensive than, in-person treatment, a new study has concluded.

RNAi Successfully Treats Degenerative Brain Disease in Mice

Geneticists led by professor Beverly Davidson at the University of Iowa have cured mice of spinocerebellar ataxia type 1 (SCA1), a genetics-based neurodegenerative disease similar to Huntington’s, using RNA interference (RNAi), which interferes with a cell’s ability to make deleterious proteins. Small sequences of RNA were delivered to the animals” brain cells via a harmless carrier virus. Mice with the SCA1 gene that received the gene therapy had normal coordination and movement and the progression of their disease was “essentially halted,” as Davidson put it.

“It was almost unbelievable” how could the simple methods that we were using lead to such a profound impact on the disease in these mice?” The researchers believe RNAi could also work against Alzheimer’s and other neurodegenerative disorders. Before that, though, they have to demonstrate that the technique will work in humans.

Reference: Lurie, Karen (2004). “Brain Disease Blocker.” ScienCentral News, August 24.

Pharmacogenomics from Iceland

Eight years ago, Iceland’s deCode Genetics mounted “a nationwide hunt for the genes that underlie heart disease, diabetes, asthma, and other common ailments,” writes Corie Lok in an in-depth report for Technology Review. More than half the island’s population gave their DNA to deCode for analysis. The visionary effort has already resulted in a clinical trial of a new experimental drug to prevent heart attacks.

The success of that trial will mean not only deCode’s first marketable medicine and a better heart attack drug, but possibly the advent of a new generation of treatments based on a mastery of genetics, says Lok. Other drugs, including one for peripheral artery disease, are “nearing the end of the development pipeline right behind the heart attack medication, which could be on the market before the end of the decade.” Success will also provide “real-world evidence of genomics” power to transform medicine.”

One of the trial”s goals is to find a biomarker that is easily measured and accurately identifies all the people who have increased vascular inflammation that puts them at risk for a heart attack. “This is not going to diminish the complexity of medicine; it”s going to increase it,” said one of Lok’s sources.

Besides deCode”s vision, any success overall will be attributable also to Iceland’s self-contained population, good medical record-keeping, healthy investments in genetic data-mining software and DNA-reading technologies, a universal health-care system, and “a general openness to medical research,” evidenced by the willingness of more than half the island’s adult population to contribute their DNA—resulting in “enough data to tackle not just heart disease but 50 different ailments, ranging from asthma to diabetes to cancer.”

Some doubters believe that deCode’s research findings in Icelanders, and the drugs developed based on those findings, may not work for other populations, but deCode hotly disputes that and is working to show that the heart attack gene it discovered in the Icelandic population is correlated with disease in an American population”as it has already shown in a British population.

Lok’s article provides much more information about deCode’s activities, and also provides a sampling of other population-wide DNA banking and analysis projects going on around the globe.

Reference: Lok, Corie (2004). “Translating Iceland”s Genes into Medicine: Armed with the DNA of an entire nation, deCode Genetics is shaving years off the drug discovery process.” Technology Review, September.

Killing Cancer Dead

A theory gaining ground is that current surgical, radiological, and chemo therapies for cancer miss “a crucial pool of mutant cells that acts as the source of the malignancy, leaving the cancer able to rise again and again,” writes Rob Stein in the Washington Post. If that is so, then the only effective strategy is to kill “the highly specialized cells, known as cancer stem cells, that appear to give rise to the cancer in the first place” but which “are largely impervious to current treatments, enabling them to lurk silently until they repeatedly spawn new tumors, either in the same part or in other parts of the body.”

Researchers have found evidence of the existence of such malignant stem cells in breast cancer, two leukemias, and a variety of brain cancers. They appear to be mutant versions of normal stem cells, but it is not clear how they originate”perhaps as a result of genetic defects or exposure to toxins. Identifying cancer stem cells for every type of malignancy may lead to new kinds of therapies, or at least a better prognosis for the patient.

In a call to cancer researchers to re-focus their efforts toward cancer stem cells, the University of Toronto geneticist who discovered cancer stem cells for acute myelogenous leukemia told Stein that the basis for leukemia treatment is generally predicated on the idea that leukemia cells grow faster than the normal cells—but the leukemia stem cells are “resting. They behave just like a normal stem cell. They sit there and eventually will regrow the leukemia. It’s critically important to understand these leukemia stem cells so we can target them.”

A University of Rochester researcher has started to do just that, writes Stein. Having identified a molecular switch involved in cell survival that appears to be unique to leukemia stem cells and not susceptible to normal treatments (“which is why patients relapse”), he has begun testing drugs that, in the laboratory, appear highly effective at killing leukemia stem cells while sparing healthy stem cells. A preliminary trial involving leukemia patients has begun at the University of Kentucky. “It’s finally getting to the exciting point,” he said.

Reference: Stein, Rob (2004). “How to Kill Cancer So It Doesn”t Grow Back: Quest Seems as Elusive as Hercules”s Second Labor.” Washington Post, August 30.

Head/Neck Cancer-killing Support Device

After 21 years and more than $70 million in investment, Genetronics’ device for treating head and neck tumors has received US Food and Drug Administration fast-track review status, reports Terri Somers in the Union-Tribune. The MedPulser charges tumors with an electrical pulse to make them more permeable for drugs, a process called electroporation. It is currently in Phase III clinical trials to test its effectiveness in helping kill tumors of the tongue, palate, jaw, and ear. In earlier (much smaller) trials, 26 percent of tumors were eliminated completely and 32 percent showed at least a 50 percent shrinkage.

The device”s real future could be much broader than head and neck cancers. It could offer patients treatment options where fibrosis and scarring could be caused by surgery or drugs, and it could significantly enhance the development of gene therapy vaccines that would “use [large molecule] DNA as a drug to replace missing or defective genes with healthy ones,” writes Somers. Electroporation would enable the large-molecule DNA to be absorbed without resort to engineered carrier viruses that could cause side effects.

The company already has plans for trials using electroporation in the treatment of breast and other cancers. Other cancers in an early stage of targeting at Genetronics include liver and prostate cancers, where the technology could “spare patients some of the major toxicities caused by the systemic drugs.”

Because electroporation is “a quick, one-time treatment with little recovery time, which means a shorter, if any, hospital stay,” and because drugs can find cancerous areas that may be invisible to a surgeon, it could eliminate many if not most cancer surgeries.

MedPulser is to be priced at US$20,000 for the generator and $2,000 for each single-use probe.

Reference: Somers, Terri (2004). “Tumor killer may be key for Genetronics.” Union-Tribune, August 17.

Marijuana Fights Cancer

Spanish researchers tested extracts of marijuana in mice that had brain tumors and found them effective in inhibiting the genetic expression of the VEGF (vascular endothelial growth factor) pathway. They also tested the therapy on glioblastomas taken from two patients who had not responded to conventional therapy and found that both tumors exhibited decreased VEGF levels.

Reference: Graham, Sarah (2004). “Marijuana Extract Fights Brain Cancer in Mice.” Scientific American, August 17.

Alimta Approved

The US Food and Drug Administration has approved Eli Lilly’s drug Alimta to treat advanced non-small cell lung cancer in patients who have undergone chemotherapy. It was found in clinical trials to shrink tumors as effectively as Taxotere but with fewer side effects. Alimta treatment costs patients US$3,900 per month.

The trial tested Alimta in combination with folate pills and B-12 injections, and the result was reduced side effects.

Reference: Henderson, Diedtra (2004). “FDA Approves Lung Cancer Drug Alimta.” AP via Yahoo News, August 19.

Disabled Michiganian Gets Experimental Treatment in China

For the first time in almost three decades following a bicycle accident, a Detroit man can “feel his legs, move his foot, shift his hip,” according to an article in Crain’s Detroit Business. But he had to go to China for the experimental treatment, a transplant of olfactory ensheathing glia cells at the injury site, which uses cells from aborted fetuses and would be prohibited in the US.

The patient reported he had sensory restoration within three days of the treatment, which has not yet been explained since it normally takes four to 18 months for cells to regenerate. The patient will undergo physical therapy at The Detroit Medical Center’s Rehabilitation Institute of Michigan.

Reference: Unknown (2004). “Slattery improves after experimental spinal surgery.” Crain’s Detroit Business (subscription only), August 23.

Stem Cells Used to Grow New Jawbone for Patient

German surgeons grew a new jawbone in the back muscle of a man whose cancerous jawbone had been removed, and transplanted it to his mouth. The new jawbone was created using a mesh cage, a growth chemical, and the patient’s stem-cell-rich bone marrow. It is not yet known whether the bone was created by the stem cells, nor whether the new jaw will stand the test of time, though the patient was soon able to eat his first solid meal in nine years—a bratwurst—following the transplant.

The operation, writes Emma Ross of the Associated Press, “is the first published report of a whole bone being engineered and incubated inside a patient’s body and transplanted.”

Reference: Ross, Emma (2004). “Doctors grow a new jawbone: German surgeons create mandible with stem cells in man”s back and then transplant it to his mouth.” Associated Press via the Detroit News, August 27.

New Malaria Cure

A synthetic, re-engineered version of the traditional Chinese malaria remedy artemisinin recently entered clinical trials in Britain, writes Helen Pilcher of Nature. It only needs to be taken for about three days and should be cheaper to produce than current anti-malaria drugs, which are less and less effective as the parasite develops resistance.

Artemisinin causes toxic free radicals to be released in the parasite’s gut, destroying it. The synthetic version adds extra chemical groups to the artemisinin molecule to make it water-soluble, so it can be administered orally or injected intravenously, and to make it more stable, so less of the compound is broken down before it reaches the parasite.

The new version is also more potent, killing 95-100 percent of parasites in mice within four days, versus a week for conventional artemisinin drugs. If the drug works well in the clinical trials, it may be given in combination with a second drug to kill any parasites still alive and to make it more difficult for the parasite to develop resistance.

Reference: Pilcher, Helen (2004). “Herbal medicine spawns antimalarial chemical.” news@nature.com, August 18.

Another Exoskeleton for the Closet

A Japanese lower-body exoskeleton called the Hybrid Assistive Limb (HAL)-3 will go on sale later this year, reports Akemi Nakamura in the Japan Times. We first reported on this device in October 2003, when its commercial launch was slated for Spring of this year. Its purpose is to help disabled or elderly people smoothly perform everyday activities such as walking and climbing up and down stairs.

The device has frames to support the user’s legs, motors to move the frame’s knee and hip joints, sensors to detect changes on skin surfaces (the changes indicate the wearer’s intention to move a limb), a battery, and a computer that analyzes the sensor signals and sends commands to the motors.

The hard part, said its developer, was developing the sensory intention system and achieving instantaneous reaction. Any delay would “become a drag to the user.” With a grant from the University of Tsukuba, the developer is also working on an upper-body suit. His exoskeletons, he thinks, could also find applications in sports training, enabling someone to experience the movements of a sports star by having the star wear the exoskeleton, record his movements, and play them back when the trainee dons the exoskeleton.

Reference: Nakamura, Akemi (2004). “Robot suit a culmination of sci-fi dreams: Creator of HAL-3 began career zapping frogs.” Japan Times, August 13.

VeriChip in Healthcare

The US Federal Drug Administration has begun a final review to determine whether hospitals can use VeriChip RFID (radio frequency identification) implantable chips to identify patients and/or permit hospital staff to access medical records, according to the company. The 11-millimeter chips are implanted in the fatty tissue below the right tricep. When the patient is near a VeriChip scanners, the chip transmits an ID number to the scanner, which can then be matched to a patient ID in a database.

The VeriChip is already approved for standard security applications and the financial market, and has been used in pets and other animals for years. The FDA will now focus mainly on privacy issues, to determine whether use of the chip could compromise confidential medical information.

The Italian Ministry of Health began a six-month trial of the chips in hospitals in April, and as we reported last month the Attorney General of Mexico and his staff have been implanted with the chips. Members of a club in Spain can use them as electronic wallets to buy drinks.

About 7,000 VeriChip tags have been sold, mainly outside the United States, and approximately 1,000 have been inserted in humans. They are implanted via syringe, which coats the chip with BioBond to protect it from the body and adhere it to local tissue. If removed, it becomes inactive.

Reference: Kanellos, Michael (2004). “Under-the-skin ID chips move toward U.S. hospitals.” CNET News.com, July 27.

Anti-depression “Pacemaker” Rejected by FDA

Once again* rejecting the advice of its own panel of experts, the US Food and Drug Administration has refused to approve Cyberonics’ pacemaker-like device to treat depression. The device is already approved as a treatment for epilepsy. In June, an advisory panel voted 5 to 2 to approve the device for chronically depressed patients who had failed other treatments, with “some members of the panel . . . troubled by what they saw as a lack of substantial clinical data to support the effectiveness of the device,” report Toni Clarke and Bill Berkrot for Reuters.

* We reported in the May issue that two FDA officials prevented their own expert from testifying publicly that antidepressants cause some children to become suicidal because they did not share his opinion or the findings of studies supporting that opinion.

Reference: Clarke, Toni and Bill Berkrot (2004). “Cyberonics Device Rejected; Stock Plunges.” Reuters via Yahoo News, August 12.

Needle-less Injections

A US$2,000 hand-held ultrasonic device called SonoPrep delivers painless injections by applying sound waves that open the skin pores sufficient to allow larger molecules, including those of many drugs, to pass through quickly. After 24 hours, the skin returns to normal. Recently approved by the US Food and Drug Administration, it will be used initially for applying lidocaine cream to anesthetize skin in five minutes instead of the current one hour. Its maker is developing other applications, “including fast administration of pain medications to cancer patients, dispensing flu vaccines, and continuous monitoring of diabetics” blood sugar levels,” writes Jessica Lee in the Boston Globe.

This and other efforts to develop painless, more efficient, and more targeted drug delivery methods “could make needles obsolete in medicine,” she adds. Other devices under development include an implanted wafer that slowly releases cancer drugs at the site of a brain tumor, and the Injex insulin injector that “shoots a stream of insulin so fine that it penetrates the skin without a needle.” A pediatric pain specialist told Lee he thinks the treatment could “get around delays” associated with blood work and could be especially useful for children who have had a lot of needle procedures and are afraid of them.

Reference: Lee, Jessica T. (2004). “Terrified of needles? Help is on the horizon.” Boston Globe, August 19.

Replacement Tissue for Long-haul Astronauts

British researchers with expertise in anti-cancer research gained from studying victims of Chernobyl are working to grow replacement human tissue for NASA”s scheduled 2020 Mars mission astronauts, should their tissues be damaged by radiation en route, as well as to develop medicines to prevent bone-mass loss caused by long-term space exposure and explore ways to protect astronauts from space radiation, including boosting the astronauts” own natural defense mechanisms against space radiation by boosting the immune reaction against cancer cells.

Together with NASA scientists, they will develop chip-based biosensors to detect radiation damage at a molecular and cellular level. The technology will be tested in NASA”s unmanned space mission program in 2008. Growing replacement tissue is Plan B, in case the anti-radiation methods don’t work. The research will involve combining umbilical blood and bone-marrow stem cells with tissues from adults to grow new body tissue in zero-microgravity bioreactors. The stem cells will be “instructed” to grow into blood, liver, muscle, and other cells needed to regenerate radiation-damaged tissue.

“Growing body parts on demand,” writes Lakshmi Sandhana in Wired News, is “the Holy Grail of tissue engineering.” The advantage of a weightless environment is that the stem cells can more easily form three-dimensional structures, a discovery resulting from experiments on past Shuttle missions and aboard the Mir space station. Colon-cancer cells were grown aboard the Shuttle, and cartilage tissue was grown on Mir.

Reference: Sandhana, Lakshmi (2004). “Careful With That Petri Dish.” Wired News, August 16.

New Heart Pump

Left-ventricular assist devices (LVADs) assist the heart’s left ventricle—the body’s main blood pump. The right ventricle plays a lesser but still important (in some patients, a critical) role, but there is as yet no implantable “RVAD.” (There are bedside RVAD machines, but clearly they are less desirable than an implantable RVAD.)

Right ventricular failure can cause congestion of the liver, kidneys, and abdominal organs “all of which can lead to the failure of several organs, the most typical complication of an LVAD implant,” writes Kylene Kiang in the Plain Dealer.

With a US$7 million government grant, biomed engineers at the Cleveland Clinic, which has already produced a successful LVAD, are building an implantable RVAD. An LVAD+RVAD implant could substitute for a heart transplant, and have the further benefit of not requiring anticoagulants or immune-suppression drugs.

Reference: Kiang, Kylene (2004). “Clinic heart pump getting a big boost.” Plain Dealer, August 11.

Artificial Retina

An artificial retina for victims of retinitis pigmentosa and age-related macular degeneration takes advantage of the fact that although the conditions destroy the natural retina’s light-sensing cells, the neurons that normally transmit the signals from those cells to the brain remain intact. It works by using a video camera in place of the light-sensing cells to capture the light and, bypassing the dead light receptors, stimulate the neurons to pass images to the brain. Under development at the Boston Retinal Implant Project since 1988, the artificial retina has undergone short-term human tests and may trialed by 2006 as a permanent prosthesis. Erika Jonietz describes the technology in a short article in Technology Review.

Reference: Jonietz, Erika (2004). “Demo: Artificial Retina: An electronic device implanted in the eye could restore the sight of millions.” Technology Review, September.

Telepsychiatry Works

Patients treated through telepsychiatry (i.e., videoconferencing with psychiatrists) were as satisfied and their symptoms resolved as early as those who were treated in person, a new study has concluded. Specifically, the report concluded “Remote treatment of depression by means of telepsychiatry and in-person treatment of depression have comparable outcomes and equivalent levels of patient adherence, patient satisfaction, and health care cost.”*

The trial involved 119 US military veterans with depression given eight therapy sessions over 6 months. Half the patients were assigned to telepsychiatry, the rest were treated in person. The findings “could translate into increased access to psychiatric care for people who live at a great distance from treatment centers, without compromise of the quality of treatment,” the researchers concluded, noting also that disabled or elderly people who cannot easily leave their homes, or patients with agoraphobia may also benefit from the use of telepsychiatry.

*Am J Psychiatry 161:1471-1476, August 2004.

Reference: Unknown (2004). ““Telepsychiatry” Works for Depression.” Reuters, August 23.