The Food and Drug Administration is cracking down on "unscrupulous" clinics selling unproven and potentially dangerous treatments involving stem cells.

Hundreds of clinics around the country have started selling stem cell therapies that supposedly use stem cells but have not been approved as safe and effective by the FDA, according to the agency.

"There are a small number of unscrupulous actors who have seized on the clinical promise of regenerative medicine, while exploiting the uncertainty, in order to make deceptive, and sometimes corrupt assurances to patients based on unproven and, in some cases, dangerously dubious products," FDA Commissioner Scott Gottlieb said in a statement Monday.

The FDA has taken action against clinics in California and Florida.

The agency sent a warning letter to the US Stem Cell Clinic of Sunrise, Fla., and its chief scientific officer, Kristin Comella, for "marketing stem cell products without FDA approval and significant deviations from current good manufacturing practice requirements."

The clinic is one of many around the country that claim to use stem cells derived from a person's own fat to treat a variety of conditions, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and lung and heart diseases, the FDA says.

The Florida clinic had been previously linked to several cases of blindness caused by attempts to use fat stem cells to treat macular degeneration.

The FDA also said it has taken "decisive action" to "prevent the use of a potentially dangerous and unproven treatment" offered by StemImmune Inc. of San Diego, Calif., and administered to patients at California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, Calif.

As part of that action, the U.S. Marshals Service seized five vials of live vaccinia virus vaccine that is supposed to be reserved for people at high risk for smallpox but was being used as part of a stem-cell treatment for cancer, according to the FDA. "The unproven and potentially dangerous treatment was being injected intravenously and directly into patients' tumors," according to an FDA statement.

Smallpox essentially has been eradicated from the planet, but samples are kept in reserve in the U.S. and Russia, and vaccines are kept on hand as a result.

But Elliot Lander, medical director of the California Stem Cell Treatment Centers, denounced the FDA's actions in an interview with Shots.

"I think it's egregious," Lander says. "I think they made a mistake. I'm really baffled by this."

While his clinics do charge some patients for treatments that use stem cells derived from fat, Lander says, none of the cancer patients were charged and the treatments were administered as part of a carefully designed research study.

"Nobody was charged a single penny," Lander says. "We're just trying to move the field forward."

In a written statement, U.S. Stem Cell also defended its activities.

"The safety and health of our patients are our number one priority and the strict standards that we have in place follow the laws of the Food and Drug Administration," according to the statement.

"We have helped thousands of patients harness their own healing potential," the statement says. "It would be a mistake to limit these therapies from patients who need them when we are adhering to top industry standards."

But stem-cell researchers praised the FDA's actions.

"This is spectacular," says George Daley, dean of the Harvard Medical School and a leading stem-cell researcher. "This is the right thing to do."

Daley praised the FDA's promise to provide clear guidance soon for vetting legitimate stem-cell therapies while cracking down on "snake-oil salesmen" marketing unproven treatments.

Stem-cell research is "a major revolution in medicine. It's bound to ultimately deliver cures," Daley says. "But it's so early in the field," he adds. "Unfortunately, there are unscrupulous practitioners and clinics that are marketing therapies to patients, often at great expense, that haven't been proven to work and may be unsafe."

Others agreed.

"I see this is a major, positive step by the FDA," says Paul Knoepfler, a professor of cell biology at the University of of California, Davis, who has documented the proliferation of stem-cell clinics.

"I'm hoping that this signals a historic shift by the FDA to tackle the big problem of stem-cell clinics selling unapproved and sometimes dangerous stem cell "treatments" that may not be real treatments," Knoepfler says.

More:
FDA Cracks Down On Stem-Cell Clinics Selling Unapproved Treatments - Northeast Indiana Public Radio

Scott McIntyre calls himself a walking miracle, and he wants to tell the world about it.

I was given three to six months to survive and Im 16 months in remission, said the 53-year-old South Bend man. I would love to get the story out and let people have hope. Dont give up. You never know.

On Friday, a University of Chicago Medicine marketing team shot video and still images of Scott at Shamrock Truck Sales, the semi-truck sales and service business he co-owns near LaPaz. His face will adorn billboards, digital and print ads in Chicagoland and northwest Indiana as soon as the U.S. Food and Drug Administration approves what UCM is calling a revolutionary breakthrough in cancer treatment.

If that FDA approval comes and UCM is preparing for it to come very soon UCM will have one of the only facilities in the Midwest certified to administer chimeric antigen receptor T-cell infusion, or CAR T-cell, a newer form of immunotherapy.

Video: CAR T treatment gives hope in cancer fight

In CAR T-cell therapy, a type of white blood cell called T-cells are extracted from the patients blood and modified in the lab to recognize specific cancer cells. These supercharged T-cells are then infused back into the patient, where they search out and destroy cancer cells.

The therapy, often described as a living drug because it is customized with each patients T-cells, will be marketed as Kymriah by Swiss pharmaceutical maker Novartis.

Scott was excited to hear news Wednesday that the FDA approved the same treatment for a form of childhood leukemia, meaning, he hopes, that it won't be long before it's approved for his form of cancer, diffuse large B-cell lymphoma. The FDA called the approval "historic" because it marks the first cell-based gene therapy approved in the United States.

Scott is one of 130 patients nationally in the clinical trial for his form of lymphoma, and he was the first to receive the treatment at UCM. That happened in May 2016, when he had exhausted all other options.

Scott has been feeling good for just less than a year. Chemotherapy has taken his hair three times but he has a full head of it once again. He can play an entire round of golf with his son. An avid Notre Dame football fan and season ticket holder, he had to miss each game in 2015, but plans to attend every game this season.

In May 2013, Scott noticed a painful growth in his groin area. His family doctor, Dr. Joseph Caruso, said he had developed a swollen lymph node, which could have resulted from his body trying to fight off an infection. Caruso asked him if he had recently had an infection, and Scott recounted recently stepping on a rusty nail while the roof on his home was being replaced. Caruso prescribed an antibiotic and the swelling seemed to go away.

But four months later, while in the shower, Scott noticed another lump under his arm. He went back to Caruso, who referred him to South Bend-based Beacon Health System oncologist Dr. Thomas Reid. After some scans, Reid diagnosed Stage 3 lymphoma.

Reid administered the standard treatment, four cycles of a chemotherapy regimen known as R-CHOP, an effective but highly toxic blend of drugs causing severe side effects. The fourth cycle had to be delayed because he developed appendicitis, and it was tougher than the first three.

After all of that, the cancer started growing again just two months later.

Reid referred him to Dr. Sonali Smith, professor of medicine and director of UCMs lymphoma program. Smith and her team knew the CAR T-cell therapy was being investigated in a few select centers. Their short-term goal was to keep him alive until they could be cleared to administer the clinical trial.

In February 2015, Scott received a stem-cell transplant, which went smoothly. But three months later, the cancer again started growing. Participation in two more clinical trials and some precisely targeted radiation therapy bought a little more time, but by late 2015, his lymphoma was gaining on him.

Then, in early February 2016, the UCM team received the go-ahead for the CAR T-cell treatment and began harvesting his T cells, a process that resembles dialysis. Scott said another patient had been slated to receive the treatment first, but that patient died.

It was during an appointment in May 2016, just a week before the treatment, that Scott first grasped how close he was to dying. Smith told him the treatment could cause severe side effects, including death. Five people in the trial had died.

I said, I understand. What other options do I have? Scott recalled. She says, Oh youve already surpassed all expectations. I said, What do you mean by that? And thats when she said, after the stem cell, if it comes back, life expectancy is six months. It was a rough day. On the way home I was pretty shaken up.

A little after 9:30 a.m. on May 18, 2016, Scott, sporting a Notre Dame baseball cap, was prepared for the treatment. Carefully observing was Dr. Michael Bishop, professor of medicine and director of the Hematopoietic Cellular Therapy Program at UCM, and about a dozen members of his team. A technician brought in his modified T-cells, thawed them out and infused them into Scott intravenously.

Ten minutes later, the treatment was finished. Afterward, he and his wife Cindy spent 28 days in the hospital and then were required to live in an apartment within 10 minutes of the university hospital. They were allowed to move back home to South Bend in July, about two months after the treatment.

Its incredible, Cindy said of Scotts recovery thus far. We did not realize what we were getting into, all of the risks, until days before. She (Dr. Smith) may have mentioned it but it didnt sink in. We both realized that win, lose or draw, theyre going to learn so much, just from how he responds to it.

Cindy praised how well Drs. Reid and Smith worked together between South Bend and Chicago, and how they told them just enough to be informed without telling them so much that they panicked.

She said, theres this trial, Cindy said. This is for you. You were designed for this trial and it was designed for you. We just have to keep you going until we can give it to you.

The treatment was on a Wednesday. By Friday night, his first fever came and it wasnt a surprise. Once they enter the body, each T cell multiplies rapidly, producing thousands of offspring. Then they launch a vigorous assault. All of that warfare occurring inside the body can cause severe flu-like symptoms: fever, swelling, low blood pressure.

On Sunday his fever spiked to 104 degrees. They packed him in ice around his neck and under his arms, and managed to break the fever without sending him into intensive care.

He also experienced some neurological effects, including tremors, cognitive delays and blurred vision.

Now, more than a year later, Smith still wants to see Scott every three months, and he remains very susceptible to infections because his immunity will always be compromised not from the CAR T-cell but from all of the chemotherapy. He still has some swelling because the scar tissue from three surgeries restricts the flow of lymphotic fluids.

I feel it all the time and I have very limited range of movements but it doesnt stop me, he said.

Unless the lawn needs to be mowed, then it really bothers him, she said. Some things will never change.

She said she never imagined she had married a pioneer.

I knew I had married somebody very unique, very special, but definitely not a pioneer, she said. He was the last person you ever thought would be sick. Doesnt drink. Doesnt smoke. Never had ventured on the wild side. This wasnt supposed to happen.

So far the FDA has only approved T-cell treatments for blood cancers, such as lymphoma and leukemia, but not solid tumor cancers, such as breast and colon cancer, which kill many more people. But Bishop of UCM said that day is coming. He expects those clinical trials to begin within a year or two, and receive FDA approval within about five years.

Its very exciting, Bishop said. The technology is a little more complicated but it has the potential to treat a broad spectrum of cancers. Ive been doing this for 25 years and this is one of the most significant advances Ive seen in my career.

Meanwhile, Scott will keep telling his story of hope to everyone he can, including himself. Bishop said Scott's cancer has a 10- to 20-percent chance to recur.

Youre still thinking that the other shoe can drop, Scott said. The mantra I use when negative thoughts enter my head is, Alright Scott, are you giving up? No. Are you quitting? No. Then shut up. I dont know if that will ever go away.

Read this article:
South Bend man a 'walking miracle' after cancer treatment ... - South Bend Tribune

01 Sep 2017

A paper in the September 1 Nature claims a cadre of rogue microglia are all it takes to orchestrate neurodegeneration. Researchers led by Frederic Geissmann and Omar Abdel-Wahab of Memorial Sloan Kettering Cancer Center in New York, and Marco Prinz of the University of Freiburg in Germany, induced a somatic mutation in about 10 percent of microglia that switched on ERK kinase signaling. The mice later developed a severe neurodegenerative disease that paralyzed them. The researchers determined that damaging inflammation caused by the mutated microglia was likely to blame. The findings raise the possibility that similar somatic mutations in people are responsible for a rare neurodegenerative disease that occurs inchildren.

This is a great paper for many reasons, commented Bart De Strooper of the Dementia Research Institute in the U.K. I am particularly excited about the concept of acquired genetic mosaicism as a cause of neurodegenerative disorder. The paper also shows that microglia mutations can be directly causative inneurodegeneration.

Most famous for their role in causing cancer, somatic mutations can spontaneously arise in any cell, sometimes giving it a proliferative edge. Mutations in the RAS-MEK-ERK signaling pathway, for example, can cause diseases called histiocytoses if they arise in the myeloid cell lineage, which gives rise to blood and immune cells, including macrophages and microglia. Histiocytoses manifest in different ways, including leukemias, other tumors, and malfunctions in multiple organs. Mysteriously, a small fraction of carriers also get a neurodegenerative disease that manifests between childhood and middle age, with symptoms such as cerebellar ataxia and tremor (Lachenal et al., 2006; Wnorowski et al., 2008). The reason for the neurodegeneration has been amystery.

Geissmann and colleagues speculated it could be caused by microglia descended from erythro-myeloid progenitor cells (EMPs) harboring the same RAS-MEK-ERK somatic mutations. EMPs arise in the embryonic yolk sac early in development, and give rise to microglia in the brain and macrophages in other tissues (Perdiguero et al., 2014; Feb 2015 conference news).In contrast, circulating monocytes are continually replenished by hemotopoietic stem cells (HSCs) in the bonemarrow.

Doomed During Development? Histiocytoses arise from somatic mutations in hematopoietic stem cells (HSCs, left) or in erythro-myeloid progenitor (EMP) cells (right), which give rise to macrophages and microglia. The mutant microglia may cause inflammation, leading to neurodegeneration. [Courtesy of Tarnawsky and Yoder, Nature, News & Views,2017.]

To find out if somatic mutations in EMPs could beget microglia that trigger neurodegeneration, first author Elvira Mass and colleagues induced a somatic mutation that causes histiocytoses into mice. They chose the V600E variant of the BRAF gene, a substitution that switches on ERK signaling. The researchers generated transgenic mice carrying an inducible copy of the mutated BRAF gene, which could only be switched on via tamoxifen-induced Cre recombination in EMPs. This also turned on yellow fluorescent protein so the researchers could identify the cells. At embryonic day 8.5, they injected pregnant mice with a teeny dose of the drug to ensure that only a fraction of the embryos EMPs would express the mutation. About 10 percent of tissue resident macrophages, including microglia, in the resulting offspring expressed V600E BRAF at one month ofage.

The mutant microglia took up their positions in the brain, but were different from their normal counterparts from the get-go. Those carrying the V600E BRAF expressed elevated markers of proliferation, ERK signaling, and inflammation. In one-month-old mice, these feisty microglia had yet to cause trouble, but by four months of age, the researchers noticed neurological symptoms in the mice, including loss of hind limb reflexes and shortened stride. At seven months, 90 percent of the animals were affected and by nine months 60 percent of the mice had full hind limb paralysis. These symptoms, similar to cerebellar ataxia, are common in people with cerebral histiocytoses. Feeding the mice a BRAF inhibitor starting at one month of age drastically delayed onset and slowedprogression.

Compared to wild-type mice (left), animals with induced BRAF mutations in their EMPs had an expansion of mutant microglia expressing YFP in their spinal cord (middle). Microglia also expressed the activation marker CD68 (top) and phosphorylated ERK (bottom). [Courtesy of Mass et al., Nature2017.]

The researchers next searched for pathological changes that could have triggered the disorder. In month-old mice, the researchers found signs of elevated microglial and astrocyte activation, but not neuronal death. Oddly, by immunohistochemistry using the 22C11 antibody, the researchers noticed deposits of amyloid precursor protein (APP) in the inflamed areas, a phenomenon that Geissmann attributed to release of the membrane protein from newly damaged axons. In six-month-old animals, large clusters of activated, phagocytic microglia carrying the BRAF mutation crowded in the thalamus, brain stem, cerebellum, and spinal cord. These same regions were rife with synaptic and neuronal loss, demyelination, and astrogliosis. The mutant microglia had a small proliferative advantage compared with their wild-type counterparts, but Geissmann attributed the bulk of the neuronal damage to the activation of the cells, rather than their expansion. Treatment with a BRAF inhibitor mitigated theseresponses.

Gene expression analysis of mutant microglia taken from paralyzed mice revealed the differential expression of around 8,000 genes, 80 percent of which were upregulated compared to microglia from control mice. These genes included a bevy of pro-inflammatory mediators, including cytokines, phagocytosis boosters, matrix proteins, and growthfactors.

For some reason, the thalamus, brain stem, cerebellum, and spinal cord were uniquely vulnerable to the presence of the V600E BRAF mutant cells. Tissue macrophages carrying the mutation also expanded in the liver, spleen, kidney, and lung, even more so than in the brain, but did not cause damage in those regions. Geissmann speculated that differences in the tissue microenvironment could play a role in this selective vulnerability. For example, normal liver macrophages are in a near constant state of activation, Geissmann said, so the organ is equipped to deal with them. Perhaps the posterior part of the brain is unaccustomed to constant microglial activation, he said. Indeed, chronic microglial activation occurs during AD as well, and appears to ultimately inflict damage, rather than helpfulresponses.

Finally, the researchers investigated whether patients with histiocytoses also had abnormal microglia. They analyzed postmortem brain tissue from three patients with Erdheim-Chester disease (ECD), and conducted gene expression analysis on brain biopsies from one person with Langerhans cell histiocytosis (LCH), and another with juvenile xanthogranuloma (JXG). All of these patients had neurodegenerative disease associated with their histiocytoses, which were all caused by BRAF V600E mutations. In the ECD samples, the researchers spotted abundant activated microglia gathered at sites of neuronal loss, astrogliosis, and demyelination. Compared with data from five control samples, gene expression analysis on the JXG and LCH samples revealed an upregulation of genes in the MAPK pathway, including multiple pro-inflammatorycytokines.

The findings support the idea that activated microglia wreak havoc in the brain and cause neurodegeneration in people withhistiocytoses.

For a somatic mutation to have an effect, affected cells must propagate sufficiently. EMPs proliferate during early development, making it a prime time for mutant clones to multiply, Geissmann said. Perhaps the number of mutant clones born during the EMP stage would suffice to harm neurons, he said. However, if microglia are also bestowed with a proliferative edge, this would likely exacerbate the damage, he added. Either way, Geissmann proposed that inhibitors of ERK signaling might thwart neurodegeneration when mutant microglia areinvolved.

In an accompanying editorial, Stefan Tarnawsky and Mervin Yoder at Indiana University in Indianapolis noted opportunities for better diagnosis in this scenario. When somatic mutations occur in EMPs during early development, macrophages in many regions of the body will likely carry the mutations, not just microglia in the brain. This suggests that it might be possible to collect macrophage samples from more easily accessible, non-CNS tissues to look for biomarkers when diagnosing microglia-related disease, theywrote.

What about somatic mutations that might arise later in life, when tissue resident macrophages or microglia are already nestled into their permanent residences? Though recent studies reported that microglia are relatively long-lived cells, they proliferate in response to threats (Aug 2017 news),perhaps setting the stage for expansion of mutant cells, Geissmann speculated. That said, beyond people with histiocytoses, the contribution of somatic mutations in microglia to neurodegenerative disease is unclear. De Strooper and others have reported that genetic mosaicism in neurons could cause neurodegeneration (Jul 2015 news). A major impediment to studying this phenomenon is that somatic mutations that arise in the brain go undetected in standard genomic sequencing.JessicaShugart

No Available Further Reading

View post:
Somatic SNAFUCan a Few Mutant Microglia Cause Neurodegenerative Disease? - Alzforum