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New Method Developed to Expand Blood Stem Cells for Bone Marrow Transplant

blood stem cell More than 50,000 stem cell transplants are performed each year worldwide. A research team led by Weill Cornell Medical College investigators may have solved a major issue of expanding adult hematopoietic stem cells (HSCs) outside the human body for clinical use in bone marrow transplantation — a critical step towards producing a large supply of blood stem cells needed to restore a healthy blood system.

In the journal Blood, Weill Cornell researchers and collaborators from Memorial-Sloan Kettering Cancer Center describe how they engineered a protein to amplify adult HSCs once they were extracted from the bone marrow of a donor. The engineered protein maintains the expanded HSCs in a stem-like state — meaning, they will not differentiate into specialized blood cell types before they are transplanted in the recipient’s bone marrow.

Finding a bone marrow donor match is challenging and the number of bone marrow cells from a single harvest procedure are often not sufficient for a transplant. Additional rounds of bone marrow harvest and clinical applications to mobilize blood stem cells are often required.

However, an expansion of healthy HSCs in the lab would mean that fewer stem cells need to be retrieved from donors. It also suggests that adult blood stem cells could be frozen and banked for future expansion and use — which is not currently possible.

“Our work demonstrates that we can overcome a major technical hurdle in the expansion of adult blood stem cells, making it possible, for the first time, to produce them on an industrial scale,” says the study’s senior investigator, Dr. Pengbo Zhou, professor of pathology and laboratory medicine at Weill Cornell.

If the technology by Weill Cornell passes future testing hurdles, Dr. Zhou believes bone marrow banks could take a place alongside blood banks.

“The immediate goal is for us to see if we can take fewer blood stem cells from a donor and expand them for transplant. That way more people may be more likely to donate,” Dr. Zhou says. “If many people donate, then we can type the cells before we freeze and bank them, so that we will know all the immune characteristics. The hope is that when a patient needs a bone marrow transplant to treat cancer or another disease, we can find the cells that match, expand them and use them.”

Eventually, individuals may choose to bank their own marrow for potential future use, Dr. Zhou says. “Not only are a person’s own blood stem cells the best therapy for many blood cancers, but they may also be useful for other purposes, such as to slow aging.”

A Scrambled Destruction Signal

Bone marrow is the home of HSCs that produce all blood cells, including all types of immune cells. One treatment for patients with blood cancers produced by abnormal blood cells is to remove the unhealthy marrow and transplant healthy blood stem cells from a donor. Patients with some cancers may also need a bone marrow transplant when anticancer treatments damage the blood. Bone marrow transplantation can also be used to treat other disorders, such as immune deficiency disorders.

The process of donating bone marrow, however, can be arduous and painful, requiring extraction of marrow with a needle from a large bone under general anesthesia. A donor may also need to undergo the procedure multiple times in order to provide enough stem cells for the recipient.

Because of these issues of extracting donor bone marrow, there have been a number of attempts to expand HSCs that have focused on the transcription factor HOXB4, which stimulates HSCs to make copies of themselves. “The more HOXB4 protein there is in stem cells, the more they will self-renew and expand their population,” Dr. Zhou says.

But all previous efforts are limited in their applicability. HSCs are notoriously refractory to gene transfer. Virus-based vehicles are thus far the most efficient means to deliver therapeutic genes into HSCs in the laboratory setting. In the past, scientists used a virus as a vehicle to deliver a therapeutic gene into patients with severe combined immunodeficiency disease (SCID) to correct their immune deficiency. However, four children receiving SCID gene therapy developed treatment-related leukemia due to the inability to control where the virus inserts itself in the genome, often on the so-called “hot spots” that activate oncogenes or inactivate tumor suppressor genes. Also, other investigators have shown that it is possible to directly insert HOXB4 protein into extracted bone marrow stem cells. “All you do is add a little tag to the protein, which acts like a vehicle, driving the proteins through the cell membrane, directly into the nucleus,” Dr. Zhou says. “But the half-life of the natural protein is very short — about one hour. So that means that in order to expand blood stem cells, these HOXB4 proteins have to be added all the time. Because the proteins are very costly, this process is both expensive and impractical.” blood_vessels_525

Dr. Zhou and his team, in collaboration with Dr. Malcolm A. S. Moore’s group from Memorial Sloan-Kettering Cancer Center, took a different approach. They examined why HOXB4 protein doesn’t last long in HSCs, once these cells are removed from the protective stem cell niche that they nest quietly in. They found that HOXB4 is targeted for degradation so that stem cells can start differentiating — that is, turn into different kinds of adult blood cells. “HOXB4 prevents blood stem cells from differentiating, while, at the same time, allows them to renew themselves,” Dr. Zhou says.

The researchers found that a protein, CUL4, is tasked with recognizing HOXB4 and tagging it for destruction by the cell’s protein destruction apparatus. They discovered that CUL4 recognizes HOXB4 because it “sees” a set of four amino acids on the protein. “HOXB4 carries a destruction signal that CUL4 recognizes and acts on,” Dr. Zhou says.

The research team engineered a synthetic HOXB4 protein with a scrambled destruction signal. They produced large quantities of the protein in bacteria, and then delivered the protein into human blood stem cells in the laboratory. “When you mask the CUL4 degradation signal, HOXB4’s half-life expands for up to 10 hours,” Dr. Zhou says. “The engineered HOXB4 did its job to expand the stem cell, while keeping all its stem cell properties intact. As a result, cells receiving the engineered HOXB4 demonstrated superior expansion capacity than those given natural HOXB4 protein. Animal studies demonstrated that the transplanted engineered human stem cells can retain their stem cell-like qualities in mouse bone marrow.”

Dr. Zhou says the engineered protein HOXB4 can potentially be administered every 10 hours or so to make the quantity of blood stem cells necessary for patient transplant and for banking. “This is the ultimate goal for what we are trying to achieve,” he says. “There are likely many roadblocks ahead to reach our goals, but we appear to have found ways to deal with one major hurdle of adult hematopoietic stem cell expansion.”

Cornell Center for Technology Enterprise and Commercialization (CCTEC), on behalf of Cornell University, has filed a patent application that covers the work described here. Other co-authors include Dr. Jennifer Lee, Dr. Jianxuan Zhang, Dr. Liren Liu, Dr. Yue Zhang, and Dr. Jae Yong Eom from Weill Cornell Medical College; Dr. Giovanni Morrone from the University of Catanzaro “Magna Graecia,” Catanzaro, Italy; and Dr. Jae-Hung Shieh from the Cell Biology Program, Memorial Sloan-Kettering Cancer Center.

The study was supported by grants from the National Institutes of Health (CA118085, CA098210 and NIHA12008023), the Leukemia and Lymphoma Society Scholar Award and the Irma T. Hirschl Career Scientist Award.

 

Source: http://www.sciencedaily.com, Weill Cornell Medical College

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Study Aims to Use Stem Cells to Help Save Sight of Diabetes Sufferers

Eyesight Scientists at Queen’s University Belfast are hoping to develop a novel approach that could save the sight of millions of diabetes sufferers using adult stem cells.

Currently millions of diabetics worldwide are at risk of sight loss due to a condition called Diabetic Retinopathy. This is when high blood sugar causes the blood vessels in the eye to become blocked or to leak. Failed blood flow harms the retina and leads to vision impairment and if left untreated can lead to blindness.

The novel REDDSTAR study (Repair of Diabetic Damage by Stromal Cell Administration) involving researchers from Queen’s Centre for Vision and Vascular Science in the School of Medicine, Dentistry and Biomedical Sciences, will see them isolating stem cells from donors, expanding them in a laboratory setting and re-delivering them to a patient where they help to repair the blood vessels in the eye. This is especially relevant to patients with diabetes were the vessels of the retina become damaged.

At present there are very few treatments available to control the progression of diabetic complications. There are no treatments which will improve glucose levels and simultaneously treat the diabetic complication.

The €6 million EU funded research is being carried out with NUI Galway and brings together experts from Northern Ireland, Ireland, Germany, the Netherlands, Denmark, Portugal and the US.

Professor Alan Stitt, Director of the Centre for Vision and Vascular Science in Queen’s and lead scientist for the project said: “The Queen’s component of the REDDSTAR study involves investigating the potential of a unique stem cell population to promote repair of damaged blood vessels in the retina during diabetes. The impact could be profound for patients, because regeneration of damaged retina could prevent progression of diabetic retinopathy and reduce the risk of vision loss.

“Currently available treatments for diabetic retinopathy are not always satisfactory. They focus on end-stages of the disease, carry many side effects and fail to address the root causes of the condition. A novel, alternative therapeutic approach is to harness adult stem cells to promote regeneration of the damaged retinal blood vessels and thereby prevent and/or reverse retinopathy.”

“This new research project is one of several regenerative medicine approaches ongoing in the centre. The approach is quite simple: we plan to isolate a very defined population of stem cells and then deliver them to sites in the body that have been damaged by diabetes. In the case of some patients with diabetes, they may gain enormous benefit from stem cell-mediated repair of damaged blood vessels in their retina. This is the first step towards an exciting new therapy in an area where it is desperately needed.”

The research focuses on specific adult stem-cells derived from bone-marrow. Which are being provided by Orbsen Therapeutics, a spin-out from the Science Foundation Ireland-funded Regenerative Medicine Institute (REMEDI) at NUI Galway.

The project will develop ways to grow the bone-marrow-derived stem cells. They will be tested in several preclinical models of diabetic complications at centres in Belfast, Galway, Munich, Berlin and Porto before human trials take place in Denmark.

Queen’s Centre for Vision and Vascular Science is a key focus of the University’s ambitious £140m ‘together we can go Beyond’ fundraising campaign. It is due to expand its Vision Sciences programme further when the University’s new £32m Wellcome-Wolfson Centre for Experimental Medicine opens in 2015. Along with vision, two new programmes in Diabetes and Genomics will also be established in the new Centre which is set to stimulate additional investment, lead to further global collaborations and create more opportunities for new health and biotech companies in Northern Ireland.

Source: AlphaGailileo, Queen’s University, Belfast


Ontario man’s sight restored with help of stem cells

Image When Taylor Binns slowly began going blind because of complications with his contact lenses, he started to prepare for living the rest of his life without vision. But an innovative treatment using stem cells has changed all that, and returned to him the gift of sight.

Four years ago, while on a humanitarian work mission to Haiti, Binns developed intense eye pain and increasingly blurry vision. Doctors at home couldn’t figure out what was wrong and, over the next two years, Binns slowly went legally blind, no longer able to drive or read from his textbooks at Queens University, where he was studying commerce.

“Everything you could do before was being taken away, day by day, and it got worse and worse,” he recalls.

Doctors finally diagnosed him with a rare eye disease called corneal limbal stem cell deficiency, which was causing the normal cells on Binns’ corneas to be replaced with scar tissue, leading to painful eye ulcers that clouded over his corneas.

A variety of things can cause the condition, including chemical and thermal burns to the corneas, which are the glass “domes” over the coloured part of our eyes. But it’s also thought that microbial infections and wearing daily wear contact lenses for too long without properly disinfecting them can lead to the disease, too.

Since a corneal transplant was not an option for Binns, hisdoctors at Toronto Western Hospital proposed something new: a limbal stem cell transplant.

The limbus is the border area between the cornea and the whites of the eye where the eye normally creates new epithelial cells. Since Binns’ limbus was damaged, doctors hoped that giving him healthy limbal cells from a donor would cause healthy new cells to grow over the surface.

While the treatment is available in certain centres around the U.S., Binns became the first patient to try the treatment at a new program at Toronto WesternHospital.

Though Binns knew he’d need to take anti-rejection drugs, he decided the procedure was worth a try.

“The alternative was to live in constant pain all my life,” he says. “So there really wasn’t anything to lose.”

Just like with an organ transplant, Binns’ doctors had to find a healthy match. It turned out his younger sister, Victoria, was the ideal candidate for the job.

In the operating room, doctors removed the scar tissue on Taylor’s eyes, then took some healthy stem cells from Victoria’s eyes and stitched them to the surface of Binns’ eyes. 

“Within a month he could see 20/40,” says ophthalmologist Dr. Allan Slomovic. “His last visit he was 20/20 and 20/40.”

Slomovic says “it’s extremely exciting” that the procedure was a success, “especially when you realize there is really nothing else that would have worked for him.”

Binns is now living pain-free, returning to doing everything he used to before his three-year sight loss.

“Being able to see my computer, being able to go for a walk or a drive — I am so happy for that,” he says.

The Toronto team hopes to do many more of these procedures in the future, says Dr. Sherif El Defrawy from the Canadian Ophthalmological Society and University of Toronto’s ophthalmology department.

“We are already seeing this in a number of centres across the country and you will see it more and more as we understand how to improve the success rate,” he says.

Researchers are also working on using stem cells from deceased donors and even using limbal stem cells from a patient’s own eyes. While that would require growing the cells in a lab to force them to multiply, it would also mean that patients might be able to skip anti-rejection drugs.

For Binns, the experience has been life-changing in one more important way: He has now decided to switch his studies from commerce to medicine, and hopes to go to school to become an ophthalmologist.

Toronto Western Hospital has done 6 similar procedures since Binns was treated and all were successful. Most of those patients had suffered burns to their eyes from chemical injuries and some people had been living with birth defects of the surface of the eye.

All stem cell transplants came from a living related donor.

Read more: http://www.ctvnews.ca/health/ontario-man-s-sight-restored-with-help-of-stem-cells-1.1088888#ixzz2FmwHals4

 

Source: CTV News, Avis Favaro, Elizabeth St. Philip


Cord blood stem cells help 3-year-old

A Little Rock child is the first in Arkansas to take part in an FDA trial using cord blood stem cells to treat his cerebral palsy. 

Before the injections, 3-year-old Drake Haynes was severely developmentally delayed. Now, Drake is running, jumping, playing and talking just like any other kid his age.

Drake’s mother, Nicole, says his transformation has been dramatic. “We never knew if he would smile and he does, a lot!”

Drake’s diagnosis of cerebral palsy came after suffering a stroke due to lack of oxygen to the brain during birth. “He couldn’t walk, he couldn’t talk, and he just sat there.”

Drake’s speech therapist, Barrett Feltus, saw little to no signs of improvement. “At first he wasn’t making any sounds or very few sounds. Now, he’s talking in words. He’s able to tell you what he wants and needs in a sentence.”

The Haynes say it’s all thanks to having Drake’s umbilical cord blood banked at birth. Now, Drake’s own stem cells are helping him heal. “The neurologist doing the assessment was amazed. She just kept saying, “Oh my gosh! I can’t believe he can do this.”

Feltus says she can see the light in Drake’s eyes. “He was unhappy for a while because he couldn’t communicate. Now he can, and he’s happier. He plays with the kids, and he can communicate his needs, so he’s overall a happy kid.”

The Haynes credit the cord blood stem cell injections for the difference in their happy, determined child. “It’s like a blind has been lifted on a window.”

They never thought Drake would be able to walk, talk, jump or ride a bike like the other kids his age. The Haynes say Drake’s personality transformed, and his progress gives them hope he’ll continue to get better and have a bright future.

The message the Haynes want to send other parents is to bank their babies cord blood. They say you never know when, or if, you’re going to need it. Hopefully you won’t, but just in case, they say it could be a success story like theirs.

Drake will continue with his intensive therapy. The Haynes and his therapist say they’re excited to continue seeing the improvements he’s making.

 

Source:  Fox16.com


Cord Blood Stem Cells Restore Toddler’s Hearing

A virus infection Stephanie Connor acquired during pregnancy put her unborn daughter at significant risk for brain damage and lifelong hearing loss. 

“It was traumatic,” said Connor, of LaBelle, Fl, after learning about her daughter’s condition. “It was like mourning the loss of a child.”

At age 1, baby Madeleine was completely deaf in her right ear and her hearing was severely lost in the left, said Connor. While a hearing aid helped to amplify some sounds for Madeleine, it would never fully repair the damage in her ear.

But a simple experimental procedure that Connor enrolled in for Madeleine may have restored her hearing and reversed her condition.

In January 2012, Madeleine, 2, became the first child to undergo an experimental hearing loss treatment through an FDA-approved trial at Memorial Hermann-Texas Medical Center that infused stem cells from her own banked cord blood into her damaged inner ear.

Within the last six months, Connor says she’s seen a dramatic improvement in Madeleine’s ability to hear.

“Before, when she would hear something she would look all around,” Connor said. “But now we notice that she turns in the right direction of the sound.”

Madeleine was also able to speak for the first time, Connor said.

For more than two decades, umbilical cord blood transplantation — either by a baby’s own cord blood or another’s, depending on the type of procedure — has been used to treat otherwise fatal diseases including blood disorders, immune diseases, and some types of cancers.

Infusing cord blood stem cells into the body may also have the potential to heal and regenerate damaged cells and tissues.

Regenerative therapy using cord blood stem cells is currently being studied as therapies to treat conditions including cerebral palsy and brain injury.

For the first time, doctors are experimenting with cord blood stem cells to regenerate hearing in children who have suffered hearing loss.

This yearlong study will follow 10 children, including Madeleine, ages 6 weeks to 18 months, who have acquired hearing loss and who have donated their cord blood to a registry.

“There are a number of treatments for hearing loss, but most of them rely on amplification of noises, not reversal of the hearing loss,” said Dr. Samer Fakhri, associate professor and program director in the Department of Otorhinolaryngology at Memorial Hermann-Texas Medical Center, and principal investigator of the study.

Since Madeleine is part of a study that is currently under way, it’s unclear whether Connor’s perceived improvement of Madeleine is really due to the stem cell procedure.

Madeleine has already had one follow-up appointment to test her speech and language development, which are indicators that her hearing has improved. She will have another one mid-July.

Fakhri said it’s still too early to determine whether the procedure benefitted Madeleine, or may be beneficial for other children.

“If there’s any improvement, it should be detected within six months to a year,” Fakhri said. “We can’t determine from just one child if there’s an overall benefit.”

If the study results show significant improvement overall among the collective children studied, children with acquired — not genetic — hearing loss, may be able to benefit from the procedure.

“We do not recommend that stem cells at this point now should be a treatment modality for hearing loss,” Fakhri said.

Previous studies in mice suggest long-term hearing repair after stem cell infusion. Fakhri says it’s likely that if the procedure works, children like Madeleine will have long-term restored hearing.

“The way the stem cells work is they support repair,” said Fakhri. “Once you repair the damage, there’s no suggestion that it will dwindle over time.”

Connor said the improvement she has seen so far is enough that she is grateful that she enrolled in the trial, and she hopes the study will prove to be beneficial in repairing hearing loss so other children can be treated successfully.

“As a mom of special needs, if you’re able to help a child it’s huge,” she said. “There’s nothing that can compare to giving a child back something that’s been taken away.”

Source: Lara Salahi, Good Morning America


Gene Therapy Shows Promise as Hemophilia Treatment in Animal Studies

For the first time, researchers have combined gene therapy and stem cell transplantation to successfully reverse the severe, crippling bleeding disorder hemophilia A in large animals, opening the door to the development of new therapies for human patients.

Researchers at Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine, collaborating with other institutions, report in Experimental Hematology that a single injection of genetically-modified adult stem cells in two sheep converted the severe disorder to a milder form. The journal is a publication of the Society for Hematology and Stem Cells.

“A new approach to treating severe hemophilia is desperately needed,” said lead author Christopher D. Porada, Ph.D., associate professor of regenerative medicine at Wake Forest Baptist. “About 75 percent of the world doesn’t have access to the current treatment – therapy to replace missing clotting factors. This puts patients in most of the world at risk of severe and permanent disabilities.”

Porada cautioned that challenges will need to be overcome before the treatment can be applied to humans, including that the sheep developed an immune response to the therapy that could decrease its effectiveness and duration.

There is currently no cure for the rare bleeding disorder hemophilia. People with this genetic disorder lack a protein, known as a clotting factor, needed for normal blood clotting. As a result, they may bleed for a longer time than others after an injury, as well as bleed internally, especially in joints such as the knees, ankles, and elbows. This bleeding can damage the organs and tissues and be life threatening. Even when life-threatening bleeds are prevented with replacement therapy, it doesn’t prevent smaller bleeds within the joints that can cause pain and decreased mobility.

People with hemophilia A, the most common type, are missing clotting factor VIII. For the study, the researchers used a combined stem cell/gene therapy approach to increase levels of factor VIII produced by the animals.

The scientists first inserted a gene for factor VIII into engineered mesenchymal stem cells, a type of adult stem cell. The cells – acting as a carrier for the gene – were then injected into the abdominal cavity of the sheep. The scientists selected mesenchymal stem cells to carry the gene because they have the ability to migrate to sites of injury or inflammation.

In the treated animals, the cells migrated to the joints and stopped ongoing bleeding. In addition, all spontaneous bleeding events ceased, and the existing joint damage was completely reversed, restoring normal posture and gait to these crippled animals, and enabling them to resume a normal activity level.

However, a paradox of the treatment was that while the symptoms were eliminated, the sheep developed an immune response to factor VIII, suggesting that the treatment’s effects would be reduced or shorter in duration. The scientists are currently working to learn why the immune response occurred and to develop strategies to prevent it.

“While preliminary, these findings could pave the way for a new therapy for hemophilia patients who experience debilitating bleeding in their joints,” Porada said.

The research was supported by the National Institutes of Health.

Co-authors were Graça Almeida-Porada (senior author) and Chung-Jung Kuo , both with Wake Forest Baptist; Chad Sanada, Evan Colletti, Esmail D. Zanjani, Walter Mandeville and John Hasenau, all with the University of Nevada at Reno; Robert Moot, Aflac Cancer Center and Blood Disorders Service; Christopher Doering, Emory Children’s Center Pediatrics; and H. Trent Spencer, Emory University School of Medicine.

Source: Wake Forest Baptist Medical Center


Stem Cell Therapy Helps Pets in Pain

The healing power of stem cells is now helping dogs in pain. Vets are excited about this new therapy that’s making a big difference for South Texans’ beloved pets.

Oscar is an 11-year-old Australian Terrier, an agility competitor that suffered from osteoarthritis, impacting his usual exuberant nature.
“He was starting to really slow down and he was starting to suffer,” said Oscar’s owner, Judy Larson of San Antonio.
Instead of medications that provide only marginal relief and create side effects, Larson turned to the Perrin/410 Animal Hospital for help. Doctors performed a new procedure called Adipose Stem Cell Therapy.
“We treat the fat, process it, activate it, and then inject it back into the animal the same day,” explained veterinarian Dr. Bryan Stuckey.
The procedure takes about four hours. Doctors first harvest fat tissue from the abdomen. Then, they process it and activate the stem cells. Injections back into the joint promote regeneration of the damaged areas in the bone, cartilage, ligaments and tendons.
“And with this, there is no side effect,” Stuckey said. “There’s no harmful side effect. It’s from the animal itself. It’s injected back in so there is no donor involved.”
Pets start to show improvement in two weeks, and continue to get better over the next two to three months.
“It was time going backwards,” Larson stated. “You know, his eyes cleared up. He started to grow hair again. His energy level went back up. His appetite. It was like getting my dog back.”
The cost is about $2,000. Vets say the procedure pays for itself in about two years, since dogs no longer need expensive medications and tests.
Stuckey has treated 16 dogs this way so far. He calls it a huge advancement in pain management.
“We can’t cure a bad joint, but we can fix it so it does not hurt as much,” he commented.
Stem cell therapy won’t necessarily extend a dog’s life. But vets say their quality of life will improve. And that can make all the difference for an animal in pain.

by Wendy Rigby / KENS 5

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