Stanford University scientists have identified a protein that, given before an injury, boosts stem cell response and improves healing. Priming with this protein, called hepatocyte growth factor activator (HGFA),could eventually speed recovery in cases where injury is expected, such as patients undergoing surgery.

Senior author Thomas Rando and lead author Joseph Rodgers previously showed that injury to one leg caused stem cells in the other leg to become alert. This state is different from the fully resting or fully active phases that stem cells usually assume.

To pinpoint the cause of this alert state,the researchers injected uninjured mice with blood serum from mice with a muscle injury. While this serum had the same level of HGFas serum from uninjured mice, it had higher levels of HGFA, a protein that activates HGF.Once HGF is activated, it, in turn, activates a signaling pathway in stem cells that produces proteins that make them alert,according to a statement.

In another experiment, they dosed mice with HGFA two days before injury. The treated mice scampered around on their wheels sooner than untreated mice, indicating faster muscle recovery. Their skin also healed faster than that of untreated mice.

Our research shows that by priming the body before an injury you can speed the process of tissue repair and recovery similar to how a vaccine prepares the body to fight infection, said Rodgers in the statement.

Finding new ways to stimulate stem cells is a major focus of tissue-repair research. Scientists at New York University and the University of Colorado at Boulder, for example, recentlyfound a gene that prompts adult stem cells to repair injured muscle in mice. They successfully used a drug to boost this gene in mice that did not have it.

While the direct implications of Stanford's discovery are obviousthe treatment could become a way to boost recovery for people in combat orsports, or those who have undergone surgerythe team is also interested in the role of HGF and HGFA in aging.

Stem cell activity diminishes with advancing age, and older people heal more slowly and less effectively than younger people, Rando said. The researchers want to look into the possibility of restoring youthful healing rates by activating this pathway, he said.

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'Priming' protein boosts stem cell response to injury, promotes healing - FierceBiotech

BY FRAN KRITZ

High doses of chemotherapy drugs followed by an infusion of a patient's own stem cells may result in remission for people with remitting-relapsing multiple sclerosis (MS), according to a study published online in Neurology on February 1, 2017.

The new results are from a small clinical trial, called HALT-MS, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH). Earlier results were published in the third year of the clinical trial while this new study looked at five years of data. The clinical trial included patients with relapsing-remitting MS, which is the most common form of the disease and often involves through long periods with no or only mild symptoms and occasional flare-ups or relapses. Over years, though, symptoms can worsen and progress.

Study Basics

Twenty four patients, ages 18 to 60 (17 women and 7 men) who had not responded to other MS medications, were included in the trial, which involved high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HC.) The high-dose chemotherapy weakens the immune system while transfusions of the patient's own blood stem cells can "reset" the immune system and potentially knock out MS.

Promising Results

At the end of the trial, 91 percent of patients had no disease progression, 87 percent did not relapse, and 86 percent had no signs of new lesions (scars that can indicate MS) on their brain or spinal cord. "These extended findings suggest that one-time treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS," says NIAID director Anthony S. Fauci, MD.

Some Adverse Events

Three deaths were reported among the trial participants, but they were unrelated to the transplants. Two were the result of MS progression and one was due to cardiovascular disease. The most common side effect of the treatment was infection.

More Studies Needed

More trials are needed before this can be considered a treatment for relapsing-remitting MS, say experts. "Although further evaluation of the benefits and risks of HDIT/HCT is needed, these five-year results suggest the promise of this treatment for inducing long-term, sustained remissions in patients with relapsing-remitting MS, who have a poor prognosis," says Richard Nash, MD, a hematologist with the Colorado Blood Cancer Institute and the principal investigator of the HALT-MS study.

The new clinical trial is "an important study" that "contributes to the accumulating knowledge of the possible benefits and risks ofstem cell transplantation in relapsing MS," says Bruce Bebo, PhD, executive vice president of research at the National MS Society. He added that "larger, well-controlled trials are needed to better understand who might benefit from this procedure and how it compares to the benefits of powerful immune-modulating therapies now available."

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Stem Cell Transplants May Work for MS, Study Says - LWW Journals (blog)

Heidi Wyandt, 27, puts on her coat to leave the Altoona Center for Clinical Research in Altoona, Pa., on Wednesday, March 29, 2017, where she is helping test an experimental non-opioid pain medication for chronic back pain related to a work related injury she received in 2014. With about 2 million Americans hooked on opioid painkillers, researchers and drug companies are searching for less addictive drugs to treat pain. (AP Photo/Chris Post)

Tummy tucks really hurt. Doctors carve from hip to hip, slicing off skin, tightening muscles, tugging at innards. Patients often need strong painkillers for days or even weeks, but Mary Hernandez went home on just over-the-counter ibuprofen.

The reason may be the yellowish goo smeared on her 18-inch wound as she lay on the operating table. The Houston woman was helping test a novel medicine aimed at avoiding opioids, potent pain relievers fueling an epidemic of overuse and addiction.

Vicodin, OxyContin and similar drugs are widely used for bad backs, severe arthritis, damaged nerves and other woes. They work powerfully in brain areas that control pleasure and pain, but the body adapts to them quickly, so people need higher and higher doses to get relief.

This growing dependence on opioids has mushroomed into a national health crisis, ripping apart communities and straining police and health departments. Every day, an overdose of prescription opioids or heroin kills 91 people, and legions more are brought back from the brink of death. With some 2 million Americans hooked on these pills, evidence is growing that they're not as good a choice for treating chronic pain as once thought.

Drug companies are working on alternatives, but have had little success.

Twenty or so years ago, they invested heavily and "failed miserably," said Dr. Nora Volkow, director of the National Institute on Drug Abuse.

Pain is a pain to research. Some people bear more than others, and success can't be measured as objectively as it can be with medicines that shrink a tumor or clear an infection. Some new pain drugs that worked well were doomed by side effects Vioxx, for instance, helped arthritis but hurt hearts.

Some fresh approaches are giving hope:

"Bespoke" drugs, as Volkow calls them. These target specific pathways and types of pain rather than acting broadly in the brain. One is Enbrel, which treats a key feature of rheumatoid arthritis and, in the process, eases pain.

Drugs to prevent the need for opioids. One that Hernandez was helping test numbs a wound for a few days and curbs inflammation. If people don't have big pain after surgery, their nerves don't go on high alert and there's less chance of developing chronic pain that might require opioids.

Funky new sources for medicines. In testing: Drugs from silk, hot chili peppers and the venom of snakes, snails and other critters.

Novel uses for existing drugs. Some seizure and depression medicines, for example, can help some types of pain.

The biggest need, however, is for completely new medicines that can be used by lots of people for lots of problems. These also pose the most risk for companies and patients alike.

ONE DRUG'S BUMPY ROAD

In the early 2000s, a small biotech company had a big idea: blocking nerve growth factor, a protein made in response to pain. The company's drug, now called tanezumab (tah-NAZE-uh-mab), works on outlying nerves, helping to keep pain signals from muscles, skin and organs from reaching the spinal cord and brain good for treating arthritis and bad backs.

Pfizer Inc. bought the firm in 2006 and expanded testing. But in 2010, some people on tanezumab and similar drugs being tested by rivals needed joint replacements. Besides dulling pain, nerve growth factor may affect joint repair and regeneration, so a possible safety issue needed full investigation in a medicine that would be the first of its type ever sold, said one independent expert, Dr. Jianguo Cheng, a Cleveland Clinic pain specialist and science chief for the American Academy of Pain Medicine.

Regulators put some of the studies on hold. Suddenly, some people who had been doing well on tanezumab lost access to it. Phyllis Leis in Waterfall, a small town in south-central Pennsylvania, was one.

"I was so angry," she said. "That was like a miracle drug. It really was. Unless you have arthritis in your knees and have trouble walking, you'll never understand how much relief and what a godsend it was."

Her doctor, Alan Kivitz of Altoona Center for Clinical Research, has helped run hundreds of pain studies and consults for Pfizer and many other companies. "You rarely get people to feel that good" as many of them did on the nerve growth factor drugs, he said.

A drug with that much early promise is unusual, said Ken Verburg, who has led Pfizer's pain research for several decades.

"When you do see one, you fight hard to try to bring one to the market," he said.

An independent review ultimately tied just a few serious joint problems to tanezumab and the suspension on testing was lifted in August 2012. But a new issue nervous system effects in some animal studies prompted a second hold later that year, and that wasn't lifted until 2015.

Now Eli Lilly & Co. has joined Pfizer in testing tanezumab in late-stage studies with 7,000 patients. Results are expected late next year about 17 years after the drug's conception.

AVOIDING PAIN TO AVOID DRUGS

What if a drug could keep people from needing long-term pain relief in the first place? Heron Therapeutics Inc. is testing a novel, long-acting version of two drugs the anesthetic bupivacaine and the anti-inflammatory meloxicam for notoriously painful operations like tummy tucks, bunion removal and hernia repair.

Company studies suggest it can numb wounds for about three days and cut patients' need for opioids by 30 to 50 percent.

There's a good chance of preventing brain responses that lead to chronic pain if patients can get through that "initially very rough period," said Dr. Harold Minkowitz, a Houston anesthesiologist who consults for Heron and treated Hernandez in the tummy tuck study.

Hernandez was part of an experiment testing the drug versus a placebo and doesn't know whether she got the drug or a dummy medicine. But she hurt less than she expected to and never filled a prescription for pain pills.

"The goal would be to have half or more of patients not requiring an opiate after they go home," said Heron's chief executive, Barry Quart. "You have far fewer opiates going out into society, far fewer opiates sitting in medicine cabinets that make their way to a high school."

Studies so far are mid-stage too small to prove safety and effectiveness but Heron plans more aimed at winning approval.

ON THE HORIZON

Many companies have their eyes on sodium channel blockers, which affect how nerves talk to each other and thus might help various types of pain. Others are testing cell therapies for nerve pain. Stem cells can modulate immune responses and inflammation, and may "overcome a raft of problems," said Cheng of the pain medicine academy.

Some companies, including Samumed, Centrexion Therapeutics and Flexion Therapeutics, are testing long-acting medicines to inject in knees to relieve arthritis pain. Samumed's aims to regenerate cartilage.

And then there's marijuana. A cannabis extract is sold as a mouth spray in Britain for nerve pain and other problems from multiple sclerosis. But cannabinoid research in the U.S. has been hampered by marijuana's legal status. A special license is needed and most researchers don't even try to obtain one, said Susan Ingram, a neurosurgery scientist at Oregon Health & Science University.

She is studying cannabinoid receptors in the brain, looking at how pain affects one type but not another. Such work might someday lead to drugs that relieve pain but don't produce a high or addiction.

Selective activity has precedent: The drug buprenorphine partially binds to opioid receptors in the brain and has become "an extraordinarily successful medication" for treating addiction, said Volkow, of the national drug institute.

"It has shown pharmaceutical companies that if you come up with a good intervention, there is an opportunity to recover their costs," she said.

___

Marilynn Marchione can be followed at http://twitter.com/MMarchioneAP

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Overcoming Opioids: The quest for less addictive drugs - Colorado Springs Gazette

JP and Annamarie Kealy plan to climb to Mt. Everest Base Camp in Nepal to raise money for the Multiple Myeloma Research Foundation. Jeannette Ross photo

Three years ago, JP Kealy was lifting weights and hurt his back. But it was more than just your typical pain, so he went to an orthopedist, who ordered an MRI.

What they found was a surprise. His bones were untypically brittle for a 48-year-old man. Blood work confirmed he had multiple myeloma, a cancer formed by malignant plasma cells.

Although the diagnosis on April 21, 2014, was devastating, Kealys wife, Annamarie, said the couple consider themselves lucky.

Most people are not diagnosed until the disease has progressed and they are in kidney failure, she said at the couples home in Wilton. We had the gift of time, spending the last three years waiting and watching.

Now they are fighting the disease head-on from two fronts: personally and publicly. Next March, JP and Annamarie will climb to Mt. Everest Base Camp in the Himalayas in a fund-raising program for the Multiple Myeloma Research Foundation called Moving Mountains for Myeloma.

The point of the expedition, Annamarie said, is to show that patients can climb mountains literally and figuratively.

Multiple myeloma is a very complicated cancer, she said, and when Kealy was diagnosed they saw four doctors and got four opinions for going forward. Kealy received monthly IV treatments to strengthen his bones, but last year his numbers reached a point where he needed chemotherapy. He recently completed a six-month course of drugs at Stamford Hospital, which he tolerated very well.

But that is not all Kealy needs.

A stem cell transplant is the best chance for remission, Annamarie said, and so on April 17 they will go to Mount Sinai Hospital for a transplant.

Doctors have already collected 20 million stem cells from Kealy through a process that took four eight-hour days. Kealy lay with his arms straight out and with one needle as big as a turkey baster, Annamarie said, that drew his blood. The stem cells were then collected and the rest of his blood was returned through another needle into his other arm.

The stem cells enough for four treatments are now frozen. They can last in that state 10 to 15 years.

When he goes to Mount Sinai, Kealy will be given a high-dose chemotherapy treatment to reduce his immunity to zero. Then his stem cells will be thawed and returned.

He will remain in a sterile environment for three weeks, with Annamarie as a caregiver, before returning home for two to three months. When home, he will be on an anti-microbial diet that Annamaria must prepare for him. That means, among other things, no raw fruits or vegetables except fruits with thick skins like bananas and oranges or red meat.

He will also need all new immunizations.

Since there is no cure as yet, the goal is complete remission, but for how long is not known.

When the Kealys first learned of his diagnosis they connected with the Multiple Myeloma Research Foundation (themmrf.org), formed in New Canaan in 1998 by twin sisters Kathy Giusti and Karen Andrews soon after Giusti was diagnosed. She was given two years to live, Annamarie said, but that was almost 20 years ago.

The support we have received from them is incredible, Annamarie said. For the last three years, the couple has participated in the organizations fund-raising 5K walk, but they wanted to do more.

Last year they started Moving Mountains and the first trip was to Mt. Kilimanjaro, Annamarie said. Typically, only one person per family is accepted for an expedition, but as Annamarie said, Ive been with him throughout. Its been such a life-changing experience. Our motto has always been JP Strong.

She wrote a letter to the organization explaining why they should go as a patient-caregiver team, and they were accepted. Because the expedition is a fund-raiser, with proceeds going to research, they were required to raise $10,000. In seven weeks they have raised more than $25,000. To contribute, visit https://endurance.themmrf.org/2018Everest/jpstrong.

For me, its something were doing thats proactive. We have four kids. I want them to see they can be resilient, she said. Their children are Tommy, a junior at the College of William and Mary; Brendan, a student at Dickinson College; Jake, a senior at Fairfield Prep; and Lily, a sophomore at Wilton High School.

Assuming he will be well enough by then, the couple will go on a training climb in Colorado in July, where they will surmount a 14,000-foot peak and meet their fellow travelers.

Next March, they will fly into Kathmandu and then to Lukla, Nepal. They will stay at Nepalese teahouses to get acclimated, and then with yaks to carry their gear and Sherpas to guide them, the group of 16 doctors, patients and caregiver will ascent to Mt. Everest Base Camp at 18,519 feet in altitude.

Its a small group of people, but the impact will be huge, she said. They will carry a banner proclaiming the Bennett Cancer Center at Stamford Hospital.

Kealy said he wasnt surprised at his wifes plan for them to participate in the climb.

I wasnt surprised she did it, he said. Theres no talking her out of it. Im glad were doing it together.

Annamarie and JP arent the only Kealys working to support the MMRF. Daughter Lily will hold a bake sale at the Village Market on Sunday, April 23. Last year she raised more than $1,000 for the organization.

This wasnt the master plan, Annamarie admitted, but added there has been an upside. Theres been a lot of good people whove come out of the woodwork. We are so positive because we have such a team rallying behind us.

Link:
Climbing mountains for cancer research - The Wilton Bulletin