US FDA steps up scrutiny of stem cell therapies – Reuters

(Reuters) - The U.S. Food and Drug Administration (FDA) is stepping up efforts to better regulate an emerging field of medicine that holds significant promise for curing some of the most troubling diseases by using the body's own cells.

A small number of "unscrupulous actors" have seized on the promise of regenerative medicine and stem cell therapies to mislead patients based on unproven, and in some cases, dangerously dubious products, the FDA said on Monday. (bit.ly/2iB4Xls)

Regenerative medicine makes use of human cells or tissues that are engineered or taken from donors. Health regulators have approved some types of stem cell transplants that mainly use blood and skin stem cells after clinical trials found they could treat certain types of cancer and grow skin grafts for burn victims.

But many potential therapies are still in the earliest stages of development. These therapies are sometimes advertised with the promise of a cure, but they often have scant evidence backing their efficacy or safety.

The FDA said it had taken steps to tackle the problem of some "troubling products" being marketed in Florida and California.

Federal officials on Friday seized from San Diego-based StemImmune Inc vials containing hundreds of doses of a vaccine reserved only for people at high risk for smallpox, the FDA said. (bit.ly/2wC1DMU)

The seizure followed recent FDA inspections that confirmed the vaccine was used to create an unapproved stem cell product, which was then given to cancer patients, the agency added.

The FDA also sent a warning letter to a Sunrise, Florida-based clinic for marketing stem cell products without regulatory approval and for major deviations from current good manufacturing practices. (bit.ly/2giGlx9)

The health regulator will present a new policy framework this fall that will more clearly detail the "rules of the road" for regenerative medicine, FDA Commissioner Scott Gottlieb, a cancer survivor, said in a statement.

Reporting by Natalie Grover in Bengaluru; Additional reporting by Tamara Mathias; Editing by Sai Sachin Ravikumar

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Stem Cell Treatment Helps Puppies With Spina Bifida – Technology Networks

A pair of English bulldog puppies are the first patients to be successfully treated with a unique therapy a combination of surgery and stem cells developed at the University of California, Davis, to help preserve lower-limb function in children with spina bifida.

Because dogs with the birth defect frequently have little control of their hindquarters, they also have little hope for a future. They are typically euthanized as puppies.

At their postsurgery re-check at 4 months old, however, the siblings, named Darla and Spanky, showed off their abilities to walk, run and play to their doctor, veterinary neurosurgeon Beverly Sturges.

The initial results of the surgery are promising, as far as hind limb control, said Sturges. Both dogs seemed to have improved range of motion and control of their limbs.

The dogs have since been adopted, and continue to do well at their home in New Mexico.

A major step toward curing spina bifida

Spina bifida occurs when spinal tissue improperly fuses in utero, causing a range of cognitive, mobility, urinary and bowel disabilities in about 1,500 to 2,000 children born in the U.S. each year. The dogs procedure, which involved surgical techniques developed by fetal surgeon Diana Farmer of UC Davis Health together with a cellular treatment developed by stem cell scientists Aijun Wang and Dori Borjesson, director of the universitys Veterinary Institute for Regenerative Cures, represents a major step toward curing spina bifida for both humans and dogs.

Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.

Sturges wanted to find out if the surgery-plus-stem-cell approach could give dogs closer-to-normal lives along with better chances of survival and adoption. At 10-weeks old, Darla and Spanky were transported from Southern California Bulldog Rescue to the UC Davis veterinary hospital, where they were the first dogs to receive the treatment, this time using canine instead of human PMSCs.

Another distinction for Darla and Spanky is that their treatment occurred after birth, since prenatal diagnosis of spina bifida is not performed on dogs, Sturges explained. The disorder becomes apparent between 1 and 2 weeks of age, when puppies show hind-end weakness, poor muscle tone, incoordination and abnormal use of their tails.

A unique environment for collaborative research

UC Davis is the only place where this type of cross-disciplinary, transformational medicine could happen, according to Farmer.

Its rare to have a combination of excellent medical and veterinary schools and strong commitment to advancing stem cell science at one institution, she said.

UC Davis is also home to the One Health initiative aimed at finding novel treatments like these for diseases that affect both humans and animals.

Ive often said that I have the greatest job on the planet, because I get to help kids, Farmer said. Now my job is even better, because I get to help puppies too.

Hopes for clinical trials in humans and dogs

With additional evaluation and U.S. Food and Drug Administration approval, Farmer and Wang hope to test the therapy in human clinical trials. Sturges and Borjesson hope to do the same with a canine clinical trial. They hope the outcomes of their work help eradicate spina bifida in dogs and humans.

In the meantime, the team wants dog breeders to send more puppies with spina bifida to UC Davis for treatment and refinements that help the researchers fix an additional hallmark of spina bifida incontinence. While Darla and Spanky are very mobile and doing well on their feet, they still require diapers.

Further analysis of their progress will determine if the surgery improves their incontinence conditions, Sturges said.

Funding for this project was provided by the Veterinary Institute for Regenerative Cures (VIRC) at the UC Davis School of Veterinary Medicine, and the Surgical Bioengineering Lab at the UC Davis School of Medicine. Private donations to the veterinary school for stem cell research also contributed to this procedure. Farmer and Wangs spina bifida research is supported by funding from the National Institutes of Health, the California Institute for Regenerative Medicine, Shriners Hospitals for Children and the March of Dimes Foundation.

This article has been republished frommaterialsprovided byUC Davis. Note: material may have been edited for length and content. For further information, please contact the cited source.

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ICMR’s stem cell research guidelines soon to be released – ETHealthworld.com

Representative imageBy Priyanka V Gupta

New Delhi: Indian Council of Medical Research (ICMR) will soon release the final document on guidelines for stem cell research, the draft of which was available on the ICMR and the DBT (Department of Biotechnology) websites for public reviews till July 31 this year. The guidelines are expected to help in curbing the unethical practices in regenerative medicine. The information was shared by Dr Geeta Jotwani, deputy director general, ICMR, at a recent event where MoU was signed between ABLE (Association of Biotechnology Led Enterprise) and FIRM (Forum for Innovative Regenerative Medicine) for industry research collaborations.

Dr Jotwani said, On the directives of DCGI (Drug Controller General of India), ICMR has been framing the guidelines for stem cell research and therapy since 2001. Unfortunately, there is no therapy available other than bone marrow transplantation, for which also no standard of care has been laid out. In that direction, we have been making periodic efforts by releasing the guideline documents in 2002, 2007, 2013 and now the updated documentation for 2017 is under finalization.

ICMR has been proactively working towards educating the stakeholders about the ethical practices in stem cell research and therapy, for which a special committee, called National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT), has been formed to advise the scientists community. Regenerative medicine is an innovative science. As part of ICMR, more research is involved than getting into conclusion that we are ready for application. We are proactively making efforts to educate, create awareness and give directions to our scientists community and clinicians on how they should go about the research part of stem cell therapy, said Dr Jotwani.

There are many clinicians entering into unethical practices and promising general public about the available care in almost all sorts of incurable conditions, including autism, according to Dr Jotwani.

She said, We are always concerned about what the end users are getting and the promises that are being made to them. Hence, we are proactively being involved in interacting with different government agencies as well as the industry to curb the unethical practices for which we also established NAC-SCRT under the Department of Health Research, Government of India. The committee, which comprises of different government agencies as well as ethics and social groups, legal experts, representatives of drug controllers office and CDSCO (Central Drug Standard Control Organization), deliberates on the issues of upcoming technologies and takes proactive role in the regenerative medicine.

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ICMR's stem cell research guidelines soon to be released - ETHealthworld.com

‘Beating Heart’ Patch Offers New Hope for Desperately Ill Patients – NBCNews.com

Aug.25.2017 / 10:24 AM ET

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From clot-busting drugs to bypass surgery, cardiologists have many options for treating the 700,000-plus Americans who suffer a heart attack each year. But treatment options remain limited for the 5.7 million or so Americans who suffer from heart failure, an often debilitating condition in which damage to the heart (often resulting from a heart attack) compromises its ability to pump blood.

Severe heart damage can pretty much incapacitate people, says Dr. Timothy Henry, director of cardiology at the Cedars-Sinai Medical Center in Los Angeles. You cant climb a flight of stairs, youre fatigued all the time, and youre at risk of sudden cardiac arrest.

Medication is available to treat heart failure, but its no panacea. And some heart failure patients undergo heart transplantation, but it remains an iffy proposition even 50 years after the first human heart was transplanted in 1967.

But soon, there may be another option.

A patch for the heart

Researchers are developing a new technology that would restore normal cardiac function by covering scarred areas with patches made of beating heart cells. The tiny patches would be grown in the lab from patients own cells and then surgically implanted.

The patches are now being tested in mice and pigs at Duke University, the University of Wisconsin and Stanford University. Researchers predict they could be tried in humans within five years with widespread clinical use possibly coming within a decade.

The hope is that patients will be again to live more or less normally again without having to undergo heart transplantation which has some serious downsides. Since donor hearts are in short supply, many patients experiencing heart failure die before one becomes available. And to prevent rejection of the new heart by the immune system, patients who do receive a new heart typically must take high doses of immunosuppressive drugs.

Heart transplants also require bypass machines which entails some risk and complications, says Dr. Timothy Kamp, co-director of the University of Wisconsins Stem Cell and Regenerative Medicine Center and one of the researchers leading the effort to create heart patches. Putting a patch on doesnt require any form of bypass, because the heart can continue to pump as it is.

To create heart patches, doctors first take blood cells and then use genetic engineering techniques to reprogram them into so-called pluripotent stem cells. These jack-of-all-trade cells, in turn, are used to create the various types of cells that make up heart muscle. These include cardiomonocytes, the cells responsible for muscle contraction; fibroblasts, the cells that give heart tissue its structure; and endothelial cells, the cells that line blood vessels.

These cells are then grown over a tiny scaffold that organizes and aligns them in a way that they become functional heart tissue. Since the patches would be made from the patients own blood cells, there would be no chance of rejection by the patients immune system.

Once the patch tissue matures, MRI scans of the scarred region of the patients heart would be used to create a digital template for the new patch, tailoring it to just the right size and shape. A 3D printer would then be used to fabricate the extracellular matrix, the pattern of proteins that surround heart muscle cells.

The fully formed patch would be stitched into place during open-heart surgery, with blood vessel grafts added to link the patch with the patients vascular system.

In some cases, a single patch would be enough. For patients with multiple areas of scarring, multiple patches could be used.

Inserting patches will be delicate business, in part because scarring can render heart walls thin and susceptible to rupture. Researchers anticipate that heart surgeons will look at each case individually and decide whether it makes more sense to cut out the scarred area and cover the defect with a patch or simply affix the patch over the scarred area and hope that, over time, the scars will go away.

Another challenge will be making sure the patches contract and relax in synchrony with the hearts onto which theyre grafted. We think this will happen because cells of the same type like to seek each other out and connect over time, Kamp says. We anticipate that if the patch couples with the native heart tissue, the electrical signals which pass through the heart muscle like a wave and tell it to contract, will drive the new patch to contract at the same rate.

How much would it cost to patch a damaged heart? Researchers put the price tag at about $100,000. Thats far less than the $500,000 or so it costs give a patient a heart transplant. And regardless of the cost, researchers are upbeat about the possibility of having a new way to treat heart failure.

Using these patches to repair the damaged muscle is likely to be very effective, says Henry. Were not quite there yet itll be a few years before you see the first clinical trials. But this technology may really provide a whole new avenue of hope for people with these conditions who badly need new treatment options.

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Stem cell treatment for children with spina bifida helps dogs first – Phys.Org

August 25, 2017 by Karen Finney An English bulldog undergoes surgery for spina bifida at the UC Davis Veterinary Medical Teaching Hospital. The dog is part of a pair of puppies being treated for spina bifida through a combination of stem cell therapy and surgery, research made possible through collaboration between the UC Davis School of Veterinary Medicine and UC Davis Health. Credit: Gregory Urquiaga/UC Davis

A pair of English bulldog puppies are the first patients to be successfully treated with a unique therapya combination of surgery and stem cellsdeveloped at the University of California, Davis, to help preserve lower-limb function in children with spina bifida.

Because dogs with the birth defect frequently have little control of their hindquarters, they also have little hope for a future. They are typically euthanized as puppies.

At their postsurgery re-check at 4 months old, however, the siblings, named Darla and Spanky, showed off their abilities to walk, run and play to their doctor, veterinary neurosurgeon Beverly Sturges.

"The initial results of the surgery are promising, as far as hind limb control," said Sturges. "Both dogs seemed to have improved range of motion and control of their limbs."

The dogs have since been adopted, and continue to do well at their home in New Mexico.

A major step toward curing spina bifida

Spina bifida occurs when spinal tissue improperly fuses in utero, causing a range of cognitive, mobility, urinary and bowel disabilities in about 1,500 to 2,000 children born in the U.S. each year. The dogs' procedure, which involved surgical techniques developed by fetal surgeon Diana Farmer of UC Davis Health together with a cellular treatment developed by stem cell scientists Aijun Wang and Dori Borjesson, director of the university's Veterinary Institute for Regenerative Cures, represents a major step toward curing spina bifida for both humans and dogs.

Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.

Sturges wanted to find out if the surgery-plus-stem-cell approach could give dogs closer-to-normal lives along with better chances of survival and adoption. At 10-weeks old, Darla and Spanky were transported from Southern California Bulldog Rescue to the UC Davis veterinary hospital, where they were the first dogs to receive the treatment, this time using canine instead of human PMSCs.

Another distinction for Darla and Spanky is that their treatment occurred after birth, since prenatal diagnosis of spina bifida is not performed on dogs, Sturges explained. The disorder becomes apparent between 1 and 2 weeks of age, when puppies show hind-end weakness, poor muscle tone, incoordination and abnormal use of their tails.

A unique environment for collaborative research

UC Davis is the only place where this type of cross-disciplinary, transformational medicine could happen, according to Farmer.

"It's rare to have a combination of excellent medical and veterinary schools and strong commitment to advancing stem cell science at one institution," she said.

UC Davis is also home to the One Health initiative aimed at finding novel treatments like these for diseases that affect both humans and animals.

"I've often said that I have the greatest job on the planet, because I get to help kids," Farmer said. "Now my job is even better, because I get to help puppies too."

Hopes for clinical trials in humans and dogs

With additional evaluation and U.S. Food and Drug Administration approval, Farmer and Wang hope to test the therapy in human clinical trials. Sturges and Borjesson hope to do the same with a canine clinical trial. They hope the outcomes of their work help eradicate spina bifida in dogs and humans.

In the meantime, the team wants dog breeders to send more puppies with spina bifida to UC Davis for treatment and refinements that help the researchers fix an additional hallmark of spina bifidaincontinence. While Darla and Spanky are very mobile and doing well on their feet, they still require diapers.

"Further analysis of their progress will determine if the surgery improves their incontinence conditions," Sturges said.

Explore further: Prenatal stem cell treatment improves mobility issues caused by spina bifida

The lower-limb paralysis associated with spina bifida may be effectively treated before birth by combining a unique stem cell therapy with surgery, new research from UC Davis Health System has found.

In a study to be presented Saturday, Jan. 28, in the oral concurrent session, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting, researchers evaluated a possible regenerative patch by using ...

In a study to be presented on Feb. 5 in an oral plenary session, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting, in Atlanta, researchers will present findings from a study titled, Cryopreserved ...

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In a study to be presented today at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting, in Dallas, Texas, researchers will report findings that show that, for children with spina bifida, surgery ...

A gene related to neural tube defects in dogs has for the first time been identified by researchers at the University of California, Davis, and University of Iowa.

"Gut bacteria get to use a lot of our food before we do," says Federico Rey, a professor of bacteriology at the University of Wisconsin-Madison. Then we get their leftoversor their waste.

A majority of shark fins and manta ray gills sold around the globe for traditional medicines come from endangered species, a University of Guelph study has revealed.

The "jumping genes" of maize have finally been mapped by an international team led by researchers at the University of California, Davis, and the Cold Spring Harbor Laboratory. The discovery could ultimately benefit the breeding ...

More evidence that our intestinal microbes are profoundly influenced by the foods we eator don't: The gut ecosystems of members of a small group of hunter-gatherers inhabiting Tanzania's Rift Valley show a strong cyclicality ...

The advent of farming, especially dairy products, had a small but significant effect on the shape of human skulls, according to a recently published study from anthropologists at UC Davis.

Biological "detectives" are tracking down biothreats such as the bacteria that causes tularemia ("rabbit fever"), but they constantly face the challenge of avoiding false positives. Sounding the alarm over a bioattack, only ...

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Yeargan Uses Patients Own Cells To Heal – Greater Wilmington Business Journal

Austin Yeargan III is on an ongoing quest to dismantle human disease.

The orthopedic sports surgeon and regenerative orthopedist is also a husband, dad and self-described motocross and surfing athlete, who likes to keep an eye on the most up-to-date techniques in his profession.

I am most excited about discovering the simplest, most natural, least invasive and most efficacious cellular- and molecular-based treatment options for patients to keep them doing what they love, Yeargan said.

At his practice, Regenerative Medicine Clinic at 5725 Oleander Drive, he uses techniques he has brought to the rapidly expanding field of regenerative medicine and orthobiologics.

Our techniques harvest, concentrate and deploy the bodys own cells for healing. Specifically, we offer patients suffering from chronic, debilitating and often immobilizing joint pain with an alternative to traditional bone and joint surgery, including total joint replacement, Yeargan said. We have developed techniques that surgeons across the country and the world have successfully duplicated, confirming the efficacy of the treatments.

His interest in this type of treatment was rooted in an early memory.

When I was 14, I was an elite-level soccer player and contest surfer, said the Raleigh native. I broke my tibia at a soccer tournament in the spring, just after receiving a new surfboard for my birthday. When the long leg cast came off in August, my knee wouldnt bend, and the limb was atrophied. Ever since then, Ive had it in the back of my mind how ridiculous it was that modern medicine couldnt make my leg heal faster or keep my knee from becoming stiff.

He was introduced to the field by the Dan Eglinton, who practiced in Asheville. Yeargan said Eglinton was the first nationally to use biologics in orthopedic surgery for hip avascular necrosis.

After receiving his science degree in chemistry at the University of North Carolina at Chapel Hill in 1993, Yeargan attended the East Carolina University School of Medicine. He completed his general surgery internship and orthopedic surgery residency at the University of Hawaii, spending six months each at the Tripler Army Medical Center and Shriners Hospital for Children.

During his time in Hawaii, he gained additional expertise through two years of clinical and bench research, focusing on cellular and molecular level changes in thermal capsulorrhaphy and cartilage injury.

Yeargan then completed a sports medicine, adult shoulder, elbow and knee fellowship with additional hand training at The Steadman Clinic in Vail, Colorado.

During Yeargans fellowship, he worked with players on several professional sports teams, including the Colorado Rockies, Denver Broncos, Denver Nuggets and the U.S. ski and snowboard teams. (More recently, Yeargan has served as a team doctor for local high schools.)

When I returned to North Carolina in 2009, I was the first surgeon in the country to use a patients own stem cells in combination with shoulder surgery, and I witnessed firsthand the positive effects, Yeargan said. The results were extraordinary, and it was then that I realized that there was about to be a massive paradigm shift in medicine.

He said he didnt necessarily make a conscious decision to pursue regenerative medicine.

I just found that I had become a regenerative orthopedic surgeon. I was so excited to read and study immunology. I think this was the biggest advancement in my knowledge base, when I realized the potential for cellular technology to dismantle human disease, as we know it, he said.

In 2010, Yeargan introduced stem cell treatment to the area.

Thanks to new ultrasound technology and instrumentation, we have been able to narrow our focus to office procedures that are minimally invasive and can be done through a tiny, 2 [millimeter] incision and with little recovery time, he said.

He said that in some settings, genetic screening, nutrition counseling and lifestyle management planning may be offered.

All of our procedures are non-operative. Our flagship procedure is the mesenchymal signaling cell concentrate that involves harvest and processing of nucleated stem cells, dendritic cells, immune cells, endothelial cells and pericytes. Yeargan said. Bone marrow is taken easily and virtually painlessly from the pelvic crest with the patient seated comfortably. Once collected, the isopycnic separator produces three distinct layers that are processed in a proprietary fashion before administration at the target site.

The procedure may be just as valuable in a 14-year-old with a cartilage injury as it is to an 87-year-old grandmother with gonarthrosis who just wants pain relief, he added.

Human cells work by signaling, Yeargan said. We think of it like medicinal signaling cells. Signaling cells respond to the environment so just the right amount of substrate will be produced by the cell until ultimately being shut down by natural feedback loops, he said.

The clinic also offers another non-surgical option for patients suffering from Achilles tendonitis, tennis and golfers elbow and plantar fasciitis. The Tenex Tenotomy System addresses those conditions.

Biologics are ideal when combined with the percutaneous Tenex procedure for tendinitis and tendinosis in most locations and contribute to the effectiveness of the procedure, Yeargan said.

The clinics Proprietary Platelet Rich Plasma procedure, or PRP+, is used to treat acute injuries primarily. It can be used for pain in areas ranging from joints to the face.

MI-EYE is camera-in-needle technology that also can be performed routinely in the office. It allows full view of the joint space for diagnosis without having to undergo an MRI, and injection procedures can be performed at the same time without changing the portal, Yeargan said.

The clinic serves about 500 patients annually.

There is definitely a growing demand for regenerative therapies in orthopedics and in general, Yeargan said. Being one of the only orthopedic surgeons specializing in non-operative orthopedics and regenerative medicine in the state, my hope is not only to educate patients about regenerative medicine but also educate the local and regional medical community as to its advantages and patient benefits.

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State’s Stem Cell Agency Awards $18.2 Million Grant for B Cell Cancer Clinical Trial – UC San Diego Health

The Independent Citizens Oversight Committee of the California Institute for Regenerative Medicine (CIRM) today unanimously approved an $18.29 million grant to University of California San Diego School of Medicine researchers to fund a phase Ib/IIa clinical trial of a novel combination drug therapy for B-cell cancers.

Scanning electron micrograph of B lymphocyte. Image courtesy of National Cancer Institute.

The approach combines an experimental monoclonal antibody-based drug called cirmtuzumab with ibrutinib, a small molecule drug that inhibits a protein called Brutons tyrosine kinase. Ibrutinib, marketed as Imbruvica, is already approved to treat B cell cancers, like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Cirmtuzumab targets ROR1, a cell surface protein present on tumors but not in normal adult tissues a distinction that makes it an attractive target for anticancer therapy. Cirmtuzumab is currently in clinical trials for the treatment of CLL.

The new combined drug trial, intended to study both safety and efficacy, is headed by Thomas Kipps, MD, PhD, Distinguished Professor of Medicine and deputy director of research at UC San Diego Moores Cancer Center, in collaboration with colleagues at the UC San Diego CIRM Alpha Stem Cell Clinic the cell therapy arm of the Sanford Stem Cell Clinical Center at UC San Diego Health.

We are very excited about evaluating this combination of targeted therapies in the clinic, said Kipps. Although ibrutinib has been approved for treatment of patients with CLL or MCL, it is exceptionally rare for this drug by itself to get rid of all the leukemia cells or cause long-lasting remissions without continuous therapy.

As a result, patients are recommended to take ibrutinib indefinitely until they develop intolerance or resistance to this drug. By blocking a survival/growth-stimulating pathway that provides a lifeline to the leukemia cells of patients taking ibrutinib, cirmtuzumab can work together with ibrutinib to potentially kill all the leukemia cells, allowing patients to achieve a complete remission and stop therapy altogether.

Kipps noted, too that cirmtuzumab targets cancer stem cells, which behave somewhat like the roots of the disease, resisting many forms of treatment and allowing a malignancy to grow back after apparently successful therapy. By targeting cancer stem cells, said Kipps, cirmtuzumab may improve our capacity to achieve more complete and longer lasting remissions when used in combination with targeted drugs, such as ibrutinib, or other anti-cancer drugs for the treatment of patients with many different types of cancer.

B cell malignancies are cancers of the blood. B cells are a type of white blood cell or lymphocyte, part of the immune system. Some B cells produce antibodies to immediately help fight off infections while others, called memory B cells, remember the pathogen in case of future infections. In B cell cancers, mutated B cells dysfunction or grow in an uncontrolled manner, resulting in diseases like CLL (the most common type of leukemia) and most non-Hodgkins lymphomas.

Cirmtuzumab was developed in Kipps laboratory under the auspices of CIRMs HALT leukemia grant awarded to Dennis Carson, MD, principal investigator, and Catriona Jamieson, MD, PhD, deputy director of the Sanford Stem Cell Clinical Center and director of stem cell research at Moores Cancer Center. Kipps led one of the six projects, generating antibodies against ROR1 that, ultimately, led to the cirmtuzumab trials in patients with CLL.

Every year around 20,000 Americans are diagnosed with CLL, said Maria Millan, MD, interim president and CEO of CIRM. For those who have run out of treatment options, the only alternative is a bone marrow transplant. Since CLL afflicts individuals in their 70's who often have additional medical problems, bone marrow transplantation carries a higher risk of life-threatening complications. The combination approach of cirmtuzumab and Ibrutinib seeks to offer a less invasive and more effective alternative for these patients.

Cirmtuzumab has also shown efficacy against solid tumors. A clinical trial is planned to test it, in combination with the drug paclitaxel, for treating metastatic breast cancer. That trial is not yet recruiting participants. Cirmtuzumabs name is a nod to CIRMs long-standing support and research funding.

CIRM was created in 2004 by California voters with $3 billion in funding support to accelerate stem cell research and treatments. Since 2004, UC San Diego researchers have received at least 96 CIRM awards, totaling more than $182 million.

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Researcher Seeks to Unravel the Brain’s Genetic Tapestry to Tackle Rare Disorder – University of Virginia

In 2013, University of Virginia researcher Michael McConnell published research that would forever change how scientists study brain cells.

McConnell and a team of nationwide collaborators discovered a genetic mosaic in the brains neurons, proving that brain cells are not exact replicas of each other, and that each individual neuron contains a slightly different genetic makeup.

McConnell, an assistant professor in the School of Medicines Department of Biochemistry and Molecular Genetics, has been using this new information to investigate how variations in individual neurons impact neuropsychiatric disorders like schizophrenia and epilepsy. With a recent $50,000 grant from the Bow Foundation, McConnell will expand his research to explore the cause of a rare genetic disorder known as GNAO1 so named for the faulty protein-coding gene that is its likely source.

GNAO1 causes seizures, movement disorders and developmental delays. Currently, only 50 people worldwide are known to have the disease. The Bow Foundation seeks to increase awareness so that other probable victims of the disorder can be properly diagnosed and to raise funds for further research and treatment.

UVA Today recently sat down with McConnell to find out more about how GNAO1 fits into his broader research and what his continued work means for all neuropsychiatric disorders.

Q. Can you explain the general goals of your lab?

A. My lab has two general directions. One is brain somatic mosaicism, which is a finding that different neurons in the brain have different genomes from one another. We usually think every cell in a single persons body has the same blueprint for how they develop and what they become. It turns out that blueprint changes a little bit in the neurons from neuron to neuron. So you have slightly different versions of the same blueprint and we want to know what that means.

The second area of our work focuses on a new technology called induced pluripotent stem cells, or iPSCs. The technology permits us to make stem cell from skin cells. We can do this with patients, and use the stem cells to make specific cell types with same genetic mutations that are in the patients. That lets us create and study the persons brain cells in a dish. So now, if that person has a neurological disease, we can in a dish study that persons disease and identify drugs that alter the disease. Its a very personalized medicine approach to that disease.

Q. Does cell-level genomic variety exist in other areas of the body outside the central nervous system?

A. Every cell in your body has mutations of one kind or another, but brain cells are there for your whole life, so the differences have a bigger impact there. A skin cell is gone in a month. An intestinal cell is gone in a week. Any changes in those cells will rarely have an opportunity to cause a problem unless they cause a tumor.

Q. How does your research intersect with the goals of the Bow Foundation?

A. Let me back up to a little bit of history on that. When I got to UVA four years ago, I started talking quite a lot with Howard Goodkin and Mark Beenhakker. Mark is an assistant professor in pharmacology. Howard is a pediatric neurologist and works with children with epilepsy. I had this interest in epilepsy and UVA has a historic and current strength in epilepsy research.

We started talking about how to use iPSCs the technology that we use to study mosaicism to help Howards patients. As we talked about it and I learned more about epilepsy, we quickly realized that there are a substantial number of patients with epilepsy or seizure disorders where we cant do a genetic test to figure out what drug to use on those patients.

Clinical guidance, like Howards expertise, allows him to make a pretty good diagnosis and know what drugs to try first and second and third. But around 30 percent of children that come in with epilepsy never find the drug that works, and theyre in for a lifetime of trial-and-error. We realized that we could use iPSC-derived neurons to test drugs in the dish instead of going through all of the trial-and-error with patients. Thats the bigger project that weve been moving toward.

The Bow Foundation was formed by patient advocates after this rare genetic mutation in GNAO1 was identified. GNAO1 is a subunit of a G protein-coupled receptor; some mutations in this receptor can lead to epilepsy while others lead to movement disorders.

Were still trying to learn about these patients, and the biggest thing the Bow Foundation is doing is trying to address that by creating a patient registry. At the same time, the foundation has provided funds for us to start making and testing iPSCs and launch this approach to personalized medicine for epilepsy.

In the GNAO1 patients, we expect to be able to study their neurons in a dish and understand why they behave differently, why the electrical activity in their brain is different or why they develop differently.

Q. What other more widespread disorders, in addition to schizophrenia and epilepsy, are likely to benefit from your research?

A. Im part of a broader project called the Brain Somatic Mosaicism Network that is conducting research on diseases that span the neuropsychiatric field. Our lab covers schizophrenia, but other nodes within that network are researching autism, bipolar disorder, Tourette syndrome and other psychiatric diseases where the genetic cause is difficult to identify. Thats the underlying theme.

See the article here:
Researcher Seeks to Unravel the Brain's Genetic Tapestry to Tackle Rare Disorder - University of Virginia

Mouse Model of Human Immune System Inadequate for Stem Cell Studies – Technology Networks

A type of mouse widely used to assess how the human immune system responds to transplanted stem cells does not reflect what is likely to occur in patients, according to a study by researchers at the Stanford University School of Medicine. The researchers urge further optimization of this animal model before making decisions about whether and when to begin wide-scale stem cell transplants in humans.

Known as humanized mice, the animals have been engineered to have a human, rather than a murine, immune system. Researchers have relied upon the animals for decades to study, among other things, the immune response to the transplantation of pancreatic islet cells for diabetes and skin grafts for burn victims.

However, the Stanford researchers found that, unlike what would occur in a human patient, the humanized mice are unable to robustly reject the transplantation of genetically mismatched human stem cells. As a result, they cant be used to study the immunosuppressive drugs that patients will likely require after transplant. The researchers conclude that the humanized mouse model is not suitable for studying the human immune response to transplanted stem cells or cells derived from them.

In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would, said Joseph Wu, MD, PhD, director of Stanfords Cardiovascular Institute and professor of cardiovascular medicine and of radiology. We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We cant do that with these animals.

Wu shares senior authorship of the research, which was published Aug. 22 in Cell Reports, with Dale Greiner, PhD, professor in the Program in Molecular Medicine at the University of Massachusetts Medical School, and Leonard Shultz, PhD, professor at the Jackson Laboratory. Former postdoctoral scholars Nigel Kooreman, MD, and Patricia de Almeida, PhD, and graduate student Jonathan Stack, DVM, share lead authorship of the study.

Although these mice are fully functional in their immune response to HIV infection or after transplantation of other tissues, they are unable to completely reject the stem cells, said Kooreman. Understanding why this is, and whether we can overcome this deficiency, is a critical step in advancing stem cell therapies in humans.

Humanized mice are critical preclinical models in many biomedical fields helping to bring basic science into the clinic, but as this work shows, it is critical to frame the question properly, said Greiner. Multiple laboratories remain committed to advancing our understanding and enhancing the function of engrafted human immune systems.

Greiner and Shultz helped to pioneer the use of humanized mice in the 1990s to model human diseases and they provided the mice used in the study. Understanding stem cell transplants

The researchers were studying pluripotent stem cells, which can become any tissue in the body. They tested the animals immune response to human embryonic stem cells, which are naturally pluripotent, and to induced pluripotent stem cells. Although iPS cells can be made from a patients own tissues, future clinical applications will likely rely on pre-screened, FDA-approved banks of stem cell-derived products developed for specific clinical situations, such as heart muscle cells to repair tissue damaged by a heart attack, or endothelial cells to stimulate new blood vessel growth. Unlike patient-specific iPS cells, these cells would be reliable and immediately available for clinical use. But because they wont genetically match each patient, its likely that they would be rejected without giving the recipients immunosuppressive drugs.

Humanized mice were first developed in the 1980s. Researchers genetically engineered the mice to be unable to develop their own immune system. They then used human immune and bone marrow precursor cells to reconstitute the animals immune system. Over the years subsequent studies have shown that the human immune cells survive better when fragments of the human thymus and liver are also implanted into the animals.

Kooreman and his colleagues found that two varieties of humanized mice were unable to completely reject unrelated human embryonic stem cells or iPS cells, despite the fact that some human immune cells homed to and were active in the transplanted stem cell grafts. In some cases, the cells not only thrived, but grew rapidly to form cancers called teratomas. In contrast, mice with unaltered immune systems quickly dispatched both forms of human pluripotent stem cells.

The researchers obtained similar results when they transplanted endothelial cells derived from the pluripotent stem cells.

A new mouse model

To understand more about what was happening, Kooreman and his colleagues created a new mouse model similar to the humanized mice. Instead of reconstituting the animals nonexistent immune systems with human cells, however, they used immune and bone marrow cells from a different strain of mice. They then performed the same set of experiments again.

Unlike the humanized mice, these new mice robustly rejected human pluripotent stem cells as well as mouse stem cells from a genetically mismatched strain of mice. In other words, their newly acquired immune systems appeared to be in much better working order.

Although more research needs to be done to identify the cause of the discrepancy between the two types of animals, the researchers speculate it may have something to do with the complexity of the immune system and the need to further optimize the humanized mouse model to perhaps include other types of cells or signaling molecules. In the meantime, they are warning other researchers of potential pitfalls in using this model to screen for immunosuppressive drugs that could be effective after human stem cell transplants.

Many in the fields of pluripotent stem cell research and regenerative medicine are pushing the use of the humanized mice to study the human immune response, said Kooreman. But if we start to make claims using this model, assuming that these cells wont be rejected by patients, it could be worrisome. Our work clearly shows that, although there is some human immune cell activity, these animals dont fully reconstitute the human immune system.

The researchers are hopeful that recent advances may overcome some of the current models limitations.

The immune system is highly complex and there still remains much we need to learn, said Shultz. Each roadblock we identify will only serve as a landmark as we navigate the future. Already, weve seen recent improvements in humanized mouse models that foster enhancement of human immune function.

This article has been republished frommaterialsprovided byStanford Medicine. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Kooreman, N. G., Almeida, P. E., Stack, J. P., Nelakanti, R. V., Diecke, S., Shao, N., . . . Wu, J. C. (2017). Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics. Cell Reports, 20(8), 1978-1990. doi:10.1016/j.celrep.2017.08.003

Read more:
Mouse Model of Human Immune System Inadequate for Stem Cell Studies - Technology Networks

Mouse model of human immune system inadequate for stem cell … – Medical Xpress

August 22, 2017 Credit: Martha Sexton/public domain

A type of mouse widely used to assess how the human immune system responds to transplanted stem cells does not reflect what is likely to occur in patients, according to a study by researchers at the Stanford University School of Medicine. The researchers urge further optimization of this animal model before making decisions about whether and when to begin wide-scale stem cell transplants in humans.

Known as "humanized" mice, the animals have been engineered to have a human, rather than a murine, immune system. Researchers have relied upon the animals for decades to study, among other things, the immune response to the transplantation of pancreatic islet cells for diabetes and skin grafts for burn victims.

However, the Stanford researchers found that, unlike what would occur in a human patient, the humanized mice are unable to robustly reject the transplantation of genetically mismatched human stem cells. As a result, they can't be used to study the immunosuppressive drugs that patients will likely require after transplant. The researchers conclude that the humanized mouse model is not suitable for studying the human immune response to transplanted stem cells or cells derived from them.

"In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would," said Joseph Wu, MD, PhD, director of Stanford's Cardiovascular Institute and professor of cardiovascular medicine and of radiology. "We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can't do that with these animals."

Wu shares senior authorship of the research, which will be published Aug. 22 in Cell Reports, with Dale Greiner, PhD, professor in the Program in Molecular Medicine at the University of Massachusetts Medical School, and Leonard Shultz, PhD, professor at the Jackson Laboratory. Former postdoctoral scholars Nigel Kooreman, MD, and Patricia de Almeida, PhD, and graduate student Jonathan Stack, DVM, share lead authorship of the study.

"Although these mice are fully functional in their immune response to HIV infection or after transplantation of other tissues, they are unable to completely reject the stem cells," said Kooreman. "Understanding why this is, and whether we can overcome this deficiency, is a critical step in advancing stem cell therapies in humans."

"Humanized mice are critical preclinical models in many biomedical fields helping to bring basic science into the clinic, but as this work shows, it is critical to frame the question properly," said Greiner. "Multiple laboratories remain committed to advancing our understanding and enhancing the function of engrafted human immune systems."

Greiner and Shultz helped to pioneer the use of humanized mice in the 1990s to model human diseases and they provided the mice used in the study.

Understanding stem cell transplants

The researchers were studying pluripotent stem cells, which can become any tissue in the body. They tested the animals' immune response to human embryonic stem cells, which are naturally pluripotent, and to induced pluripotent stem cells. Although iPS cells can be made from a patient's own tissues, future clinical applications will likely rely on pre-screened, FDA-approved banks of stem cell-derived products developed for specific clinical situations, such as heart muscle cells to repair tissue damaged by a heart attack, or endothelial cells to stimulate new blood vessel growth. Unlike patient-specific iPS cells, these cells would be reliable and immediately available for clinical use. But because they won't genetically match each patient, it's likely that they would be rejected without giving the recipients immunosuppressive drugs.

Humanized mice were first developed in the 1980s. Researchers genetically engineered the mice to be unable to develop their own immune system. They then used human immune and bone marrow precursor cells to reconstitute the animals' immune system. Over the years subsequent studies have shown that the human immune cells survive better when fragments of the human thymus and liver are also implanted into the animals.

Kooreman and his colleagues found that two varieties of humanized mice were unable to completely reject unrelated human embryonic stem cells or iPS cells, despite the fact that some human immune cells homed to and were active in the transplanted stem cell grafts. In some cases, the cells not only thrived, but grew rapidly to form cancers called teratomas. In contrast, mice with unaltered immune systems quickly dispatched both forms of human pluripotent stem cells.

The researchers obtained similar results when they transplanted endothelial cells derived from the pluripotent stem cells.

A new mouse model

To understand more about what was happening, Kooreman and his colleagues created a new mouse model similar to the humanized mice. Instead of reconstituting the animals' nonexistent immune systems with human cells, however, they used immune and bone marrow cells from a different strain of mice. They then performed the same set of experiments again.

Unlike the humanized mice, these new mice robustly rejected human pluripotent stem cells as well as mouse stem cells from a genetically mismatched strain of mice. In other words, their newly acquired immune systems appeared to be in much better working order.

Although more research needs to be done to identify the cause of the discrepancy between the two types of animals, the researchers speculate it may have something to do with the complexity of the immune system and the need to further optimize the humanized mouse model to perhaps include other types of cells or signaling molecules. In the meantime, they are warning other researchers of potential pitfalls in using this model to screen for immunosuppressive drugs that could be effective after human stem cell transplants.

"Many in the fields of pluripotent stem cell research and regenerative medicine are pushing the use of the humanized mice to study the human immune response," said Kooreman. "But if we start to make claims using this model, assuming that these cells won't be rejected by patients, it could be worrisome. Our work clearly shows that, although there is some human immune cell activity, these animals don't fully reconstitute the human immune system."

The researchers are hopeful that recent advances may overcome some of the current model's limitations.

"The immune system is highly complex and there still remains much we need to learn," said Shultz. "Each roadblock we identify will only serve as a landmark as we navigate the future. Already, we've seen recent improvements in humanized mouse models that foster enhancement of human immune function."

Explore further: Study provides hope for some human stem cell therapies

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