April 12, 2013

Regenerative Heart Medicine Could Get Boost With Nanotechnology

Researchers at the Stanford University School of Medicine have developed a new visualization technique which they believe could eventually help make the repair of damaged hearts through regenerative medicine a reality.
In a study published in Wednesday’s edition of the journal Science Translational Medicine, senior author and Stanford radiology professor Sam Gambhir and colleagues describe how they plan to mark the stem cells which would be used in the repair process.
By marking the cells, doctors would be able to track them by using standard ultrasounds as they leave the needle and enter a patient’s body. The process would allow for the stem cells to be guided to their intended destination more precisely, and would also allow doctors to monitor them using magnetic-resonance imaging (MRI) technology for several weeks afterwards, the researchers explained.
To date, both human and animal trials in which stem cells were injected into cardiac tissue to treat severe heart attacks or heart failure have been largely unsuccessful, said Gambhir.
“We’re arguing that the failure is at least partly due to faulty initial placement,” he explained in a statement. “You can use ultrasound to visualize the needle through which you deliver stem cells to the heart. But once those cells leave the needle, you’ve lost track of them.”
For this reason, scientists have been unable to precisely determine whether or not the stem cells actually reached the heart wall, and whether they remained there or diffused away from the cardiac tissue. In addition, there has been no way to determine how long the cells managed to stay alive, or if they successfully replicate and eventually develop into heart cells.
Gambhir’s team method could help answer some of those questions.
“All stem cell researchers want to get the cells to the target site, but up until now they’ve had to shoot blindly,” he said. “With this new technology, they wouldn’t have to. For the first time, they would be able to observe in real time exactly where the stem cells they’ve injected are going and monitor them afterward.”
“If you inject stem cells into a person and don’t see improvement, this technique could help you figure out why and tweak your approach to make the therapy better,” Gambhir added.
In addition to the issues surrounding the initial position of the therapeutic stem cells, tracking them once they enter the body has proven troublesome since there is no way to distinguish them from any other cell in the patient’s body. Since they normally cannot be tracked upon entering the body, if the attempt to repair the heart fails, doctors often are unable to pinpoint exactly why the process proved unsuccessful.
The new technique, however, aims to solve those problems by using extremely small nanoparticles that act as imaging agents. The nanoparticles, which have a diameter slightly less than one-third of a micron (or less that one-thirtieth the diameter of a red blood cell), are made of silica so that they can be visualized by ultrasound. Furthermore, an MRI contrast agent known as gadolinium was also added to the imaging agents.
Gambhir and his colleagues were able to successfully demonstrate that mesenchymal stem cells – a class of cells frequently used in heart-regeneration research – could store the nanoparticles without sacrificing any of their ability to survive, replicate and differentiate into living heart cells.
Lead author Jesse Jokerst, a postdoctoral scholar in Gambhir’s lab, said there were concerns that the signal would be fairly weak. However, he and his colleagues found that once they were ingested, they clumped together within the cells, reflecting the ultrasound waves far more dramatically and providing a far stronger signal than anticipated.
Despite the optimism, it will probably be at least three years before the technique can be tested in humans.

April 10, 2013

One Drug to Shrink All Tumors

A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a "do not eat" signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells.
A decade ago, biologist Irving Weissman of the Stanford University School of Medicine in Palo Alto, California, discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47, he and other scientists found, is also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, Weissman's lab showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, he and colleagues have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers.
"What we've shown is that CD47 isn't just important on leukemias and lymphomas," says Weissman. "It's on every single human primary tumor that we tested." Moreover, Weissman's lab found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient.
To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the anti-CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types.
Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment—colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped.

"We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis," says Weissman.
Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences.
Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. "The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor," he notes, "and it's possible that a real tumor has additional immune suppressing effects."
Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. "In what ways might they work together and in what ways might they be antagonistic?" Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual.
Weissman's team has received a $20 million grant from the California Institute for Regenerative Medicine to move the findings from mouse studies to human safety tests. "We have enough data already," says Weissman, "that I can say I'm confident that this will move to phase I human trials."
*Correction, 2 April 2013: One reference to the compound used to treat mice was previously named as CD47, but in all cases was the antibody to that protein, anti-CD47.