Patient stem cells used to make dementia-in-a-dish; help identify new treatment strategy

IMAGE:Induced pluripotent stem cells (iPSCs) derived from patients with frontotemporal dementia were genetically corrected and converted to cortical neurons. The green staining indicates the cortical marker CTIP2, the red stain... view more

Credit: Susanna Raitano/Stem Cell Reports 2014

Belgian researchers have identified a new strategy for treating an inherited form of dementia after attempting to turn stem cells derived from patients into the neurons most affected by the disease. In patient-derived stem cells carrying a mutation predisposing them to frontotemporal dementia, which accounts for about half of dementia cases before the age of 60, the scientists found a targetable defect that prevents normal neurodevelopment. These stem cells partially return to normal when the defect is corrected.

The study appears in the December 31st issue of Stem Cell Reports, the official journal of the International Society of Stem Cell Research published by Cell Press.

"Use of induced pluripotent stem cell (iPSC) technology"--which involves taking skin cells from patients and reprogramming them into embryonic-like stem cells capable of turning into other specific cell types relevant for studying a particular disease--"makes it possible to model dementias that affect people later in life," says senior study author Catherine Verfaillie of KU Leuven.

Frontotemporal disorders are the result of damage to neurons in parts of the brain called the frontal and temporal lobes, gradually leading to behavioral symptoms or language and emotional disorders. Mutations in a gene called progranulin (GRN) are commonly associated with frontotemporal dementia, but GRN mutations in mice do not mimic all the features of the human disorder, which has limited progress in the development of effective treatments.

"iPSC models can now be used to better understand dementia, and in particular frontotemporal dementia, and might lead to the development of drugs that can curtail or slow down the degeneration of cortical neurons," Verfaillie says.

Verfaillie and Philip Van Damme of the Leuven Research Institute for Neuroscience and Disease explore this approach in the Stem Cell Reports study by creating iPSCs from three patients carrying a GRN mutation. These immature cells were impaired at turning into mature, specialized cells called cortical neurons--the most affected cell type in frontotemporal dementia.

One of the top defective pathways in the iPSCs was the Wnt signaling pathway, which plays an important role in neuronal development. However, genetic correction or treatment with a compound that inhibits the Wnt signaling pathway restored the ability of the iPSCs to turn into cortical neurons. Taken together, the findings demonstrate that the GRN mutation causes the defect in cortical neuron formation by altering the Wnt signaling pathway.

"Our findings suggest that signaling events required for neurodevelopment may also play major roles in neurodegeneration," Van Damme says. "Targeting such pathways, as for instance the Wnt pathway presented in this study, may result in the creation of novel therapeutic approaches for frontotemporal dementia."

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Patient stem cells used to make dementia-in-a-dish; help identify new treatment strategy

Brainstorm Cell Therapeutics (BCLI) Stock Rises Ahead of ALS Treatment Trial Data Release

NEW YORK (TheStreet) -- Shares ofBrainstorm Cell Therapeutics (BCLI) soared 20.88% to $4.69 on higher-than-average volume in morning trading Wednesday ahead of the biotech company's data release on Monday.

Brainstorm intends to release the final results from its Phase 2a trial of its stem cell therapy NurOwn on Monday. The company describes NurOwn as an "autologous, adult stem cell therapy technology" designed to treat ALS, also known as Lou Gehrig's Disease.

The company will host a conference call on Monday to discuss the results.

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Brainstorm Cell Therapeutics (BCLI) Stock Rises Ahead of ALS Treatment Trial Data Release

Stem cell transplant may help patients with MS

An experimental treatment that uses a patient's own stem cells may offer new hope for people with multiple sclerosis.

In a small clinical trial, patients experienced long-term disease remission after undergoing a transplant of their own hematopoietic stem cells. This type of cell is responsible for the formation of blood in the body and are typically derived from bone marrow. The patients also took high-dose immunosuppressive drugs.

The paper, published Monday in JAMA Neurology, reports on the third year of a five-year study. A total of 24 patients with active relapsing-remitting MS were enrolled in the trial. With this type of MS, patients have points when their disease is active followed by periods when they do not experience any symptoms.

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Dr. Jon LaPook goes inside the trial and approval process for an experimental treatment using stem cells designed to make Multiple Sclerosis pati...

The researchers found that nearly 79 percent of the patients who underwent the procedure sustained full neurologic function for the three years following the treatment and symptoms of their disease did not progress. Additionally, patients in that time period did not develop any new lesions related to their disease.

More than 90 percent of patients did not experience disease progression, while 86 percent did not have any periods of relapse. Though a small number of patients did have side effects from the immunosuppressive drugs, they were no different than the side effects typically experienced by MS patients taking the drugs who haven't undergone stem cell therapy.

"Longer follow-up is needed to determine the durability of the response," the authors write in the study. "Careful comparison of the results of this investigation and other ongoing studies will be needed to identify the best approaches for high-dose immunosuppressive therapies for MS and plan the next clinical studies."

The authors of an accompanying editorial say the research indicates this type of therapy has potential to work on patients who do not experience disease remission with medications alone, such as immunosuppressive drugs and anti-inflammatory drugs such as corticosteroids.

However, they add that "the jury is still out regarding the appropriateness and indication" of stem cell transplants for MS patients. Stem cell therapy is not approved by the U.S. Food and Drug Administration for the treatment of MS. The National Multiple Sclerosis Society currently funds 15 research projects on stem cell therapies that have the potential to prevent disease activity and repair nerve damage.

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Stem cell transplant may help patients with MS

Stem Cell Therapy for MS Shows Promise

Experimental treatment kills off, then 'resets' the immune system

WebMD News from HealthDay

By Dennis Thompson

HealthDay Reporter

MONDAY, Dec. 29, 2014 (HealthDay News) -- An experimental therapy that kills off and then "resets" the immune system has given three years of remission to a small group of multiple sclerosis patients, researchers say.

About eight in 10 patients given this treatment had no new adverse events after three years. And nine in 10 experienced no progression or relapse in their MS, said lead author Dr. Richard Nash of the Colorado Blood Cancer Institute at Presbyterian/St. Luke's Medical Center in Denver.

"I think we all think of this as a viable therapy," Nash said. "We still need to perform a randomized clinical trial, but we're all pretty impressed so far, in terms of what we've seen."

In multiple sclerosis, the body's immune system for some unknown reason attacks the nervous system, in particular targeting the insulating sheath that covers the nerve fibers, according to the U.S. National Institutes of Health. People with the more common form, called relapsing-remitting MS, have attacks of worsening neurologic function followed by partial or complete recovery periods (remissions).

Over time, as the damage mounts, patients become physically weak, have problems with coordination and balance, and suffer from thinking and memory problems.

This new therapy seeks to reset the immune system by killing it off using high-dose chemotherapy, then restarting it using the patient's own blood stem cells. Doctors harvest and preserve the patient's stem cells before treatment, and re-implant them following chemotherapy.

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Stem Cell Therapy for MS Shows Promise

Stem cell registry will make cancer treatment cheaper

NEW DELHI: India may soon have an official database on stem cell donors and recipients. The health ministry is evaluating a proposal along with All India Institute of Medical Sciences (AIIMS) to create a donor registry as part of the National Health Mission (NHM), a senior official told TOI.

The proposal suggests enrolling all district hospitals in the first phase to seek stem cell details from across the country. "Once a stem cell donor registry is in place, a willing donor can be contacted and one can coordinate easily. Also, this would enhance access to safe blood," the official said.

Stem cells, found in bone marrow, are like building blocks which can grow into any normal cell of the body such as red blood cells to carry oxygen, white blood cells to fight infection, or platelets to stop bleeding.

Apart from the donor registry, the ministry is also looking at creating facilities for human leucocyte antigen (HLA) typing. HLA-typing is a process conducted for matching donors and recipients of stem cell. HLA-typing is necessary to minimize rejection of stem cell transplant, experts say.

Once created, this would be the first government registry in the country. Till now, such registries have been run in the country by a few NGOs such as Bharat Stem Cells.

According to Bharat Stem Cells, there is usually 25% chance of a patient finding a matching donor within the family. The rest depend on unrelated voluntary stem cell donors.

Stem cell therapy has been shown to be effective in various blood disorders and in treatment of cancer. It is widely used in bone marrow transplantation. However, stem cell treatment remains expensive because of limited research as well as unavailability and lack of coordination between donors and recipients. Some private hospitals charge as much as Rs 1 lakh per session for stem cell therapy. On an average, stem cell treatment is estimated to cost around Rs 15-16 lakh.

According to the official, the idea behind including stem cell into NHM is to make it affordable by creating records and providing facilities.

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Stem cell registry will make cancer treatment cheaper

More about Gordie Howe's therapy

Stem cells grown under low oxygen. These stem cells from Stemedica are licensed to CardioCell.

Dr. David Gorski, a prominent skeptic of therapies offered outside the scientifically controlled clinical trial system, has published an extensive and critical look at the stem cell therapy Gordie Howe received in early December to help him recover from a serious stroke.

I had email exchanges with Gorski while writing my article last week on the treatment, which uses stem cells provided by San Diego-based Stemedica. Gorski, whose previous blog post at Science-Based Medicine on Howe's treatment caught my attention, follows through with an analysis of the clinical trial setup used by Novastem, a Mexican stem cell company licensed by Stemedica to use its cells.

Dr. Murray Howe and his hockey great father, Gordie Howe, on a fishing trip in Saskatchewan in 2013. / Courtesy Murray Howe

"As sympathetic as I am to the Howe family, Im sorry. I reluctantly have to say that Murray Howe really should know better," Gorski wrote. "If Gordie Howe was treated as part of a clinical trial, then Novastem should have treated him for free! Thats because if it is running a clinical trial, it should treat everyone on the trial for free. Thats the way its done ethically."

I asked Novastem president Rafael Carrillo about the financial issue for my article. Carrillo said Novastem doesn't have deep pockets like a big pharmaceutical company, so it needs to charge for the treatment to pay its expenses. Without that money, it can't afford the trial. Patients wouldn't get the opportunity to get care that could help them, Carrillo said. Moreover, this arrangement is legal under Mexican law.

Gorksi views this as unethical, even if it's legal. He objects to the free treatment given to Gordie Howe, because it amounts to publicity for Novastem that will attract paying customers. And even if Howe is doing better, as appears to be the case, it's not possible to tell definitively whether stem cells helped.

The U.S. system has its own flaws, Gorski says, because patient expenses not related to the clinical trial are not paid for.

"Patients who dont have health insurance will often have a huge difficulty paying for their care not related to the clinical trial and thus will have difficulties accessing cutting-edge clinical trials because they cant pay for their own regular care," Gorski wrote. "Yay, USA!"

Stemedica is offering its own U.S. trial of the therapy, but people must have had the stroke at least six months ago. That's because people make the most improvement within six months after a stroke. So delaying treatment until after that point will make it easier to detect improvement caused by the stem cell treatment.

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More about Gordie Howe's therapy

Malones donate $42.5 million to CSU for new stem-cell research facility

John and Leslie Malone pose with Maikel at Harmony Sporthorses, December 2, 2014.

The largest ever cash donation to Colorado State University stems from a novel treatment to get a dressage horse with a bum knee back into the show ring.

John and Leslie Malone's $42.5 million gift, announced Monday, will create the CSU Institute for Biologic Translational Therapies in the College of Veterinary Medicine and Biomedical Sciences, a 100,000-square-foot facility to develop stem-cell research into commercially viable treatments for animals and humans.

"This is the largest cash gift in the history of the university and it's absolutely staggering," said Brett Anderson, CSU's vice president for advancement. "It really allows us to be the best in the nation."

The Malone money will fund half of the $65 million cost to construct the facility. The school is looking for more donations to match the Malones' contribution. So far, an additional $10 million has been raised.

The Malones also provided $10 million to cover the Institute's operating expenses once the facility is built.

"The Malones have been so gracious. We asked them if they want to put their name on the building, but they said if it's helpful to you in order to get another major donor, we are happy to let you name it for someone else," Anderson said. "They are an incredible couple."

John Malone, who made his millions at the helm of Tele-Communications Inc. and now chairs the giant Liberty Media Corp., and his wife, Leslie, could not be reached for comment on Monday.

The Malones, who raise and train dressage and jumping horses on a ranch near Kiowa, last year donated $6 million to the school to establish the Leslie A. Malone Presidential Chair in Equine Sports Medicine.

They later brought Blixt, their dressage horse with a bad knee, to the vet school's Orthopaedic Research Center.

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Malones donate $42.5 million to CSU for new stem-cell research facility

Did stem cells really help Gordie Howe?

Dr. Murray Howe and his hockey great father, Gordie Howe, on a fishing trip in Saskatchewan in 2013.

Hockey legend Gordie Howe is making a dramatic recovery from a serious stroke thanks to stem cell therapy developed by San Diego-based Stemedica, his family says. Some medical scientists aren't so sure, however.

Howe, 86, suffered the stroke in late October, leaving him unable to walk and disoriented. He began improving within hours after receiving the stem cells in early December, said Dr. Murray Howe, a radiologist and one of Howes sons. For example, Howe insisted on walking to the bathroom, which he previously could not do.

"If I did not witness my father's astonishing response, I would not have believed it myself," Murray Howe said by email Thursday. "Our father had one foot in the grave on December 1. He could not walk, and was barely able to talk or eat."

"Our father's progress continues," the email continued. "Today, Christmas, I spoke with him on FaceTime. I asked him what Santa brought him. He said 'A headache.' I told him I was flying down to see him in a week. He said, 'Thanks for the warning.'"

Howe is receiving speech and physical therapy at his home in Lubbock, Texas, and his therapists say he is much better than before receiving the stem cells.

Howe received the treatment from Novastem, a Mexican stem cell company that has licensed the use of Stemedica's cells for clinical trials approved by the Mexican government. Howe was given neural stem cells to help his brain repair damage, and stem cells derived from bone marrow to improve blood circulation in the brain. The procedure took place at Novastem's Clinica Santa Clarita in Tijuana.

Such use of unproven stem cell therapies outside the U.S. clinical trial system draws objections from some American health care professionals. They warn of the potential for abuse, say there's a lack of rigorous scientific standards, and call for tighter federal regulation of the proliferation of stem cell treatments.

Nevertheless, patients with ailments that don't response to approved treatments continue to seek such care. These patients and families say they have the right to make their own judgments. And they may not have time to wait for proof, so they're willing to take a chance.

Stemedica says it follows U.S. government law, and requires those licensing its stem cells in foreign countries to obey the laws of those countries.

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Did stem cells really help Gordie Howe?

Spectrum Pharma Submits NDA For CE-Melphalan

Spectrum Pharmaceuticals, Inc. (SPPI: Quote) said Friday that it has submitted a New Drug Application or NDA to the U.S. Food and Drug Administration for approval of Captisol-Enabled Melphalan HCl for injection to be used as a high-dose conditioning treatment prior to stem cell transplantation in patients with multiple myeloma.

Henderson, Nevada-based Spectrum Pharma is also seeking approval for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. The biotechnology company noted that the NDA submission represented an important step forward in bringing new treatment options to cancer patients.

Spectrum Pharma expects the FDA review to take about 10 months, and plans to launch the drug with its existing hematology and oncology sales force next year pending approval. The company noted that its formulation is free of propylene glycol and does not use a custom solvent for its reconstitution.

Spectrum Pharma gained global development and commercialization rights to CE-Melphalan from Ligand Pharmaceuticals Inc. (LGND: Quote) in March 2013.

The company assumed the responsibility for the pivotal clinical trial and was responsible for filing the NDA for CE-Melphalan. Under the license agreement, Ligand received a license fee and is eligible to receive milestone payments, as well as royalties following potential commercialization.

Rajesh Shrotriya, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals said, "We believe the lack of propylene glycol in the preparation of CE-Melphalan eliminates the risk of the toxicities associated with that excipient. The improved solubility and stability of this novel melphalan formulation, CE-Melphalan, will make it an attractive treatment option for both transplant conditioning, and the palliative treatment of patients with multiple myeloma who cannot take oral melphalan."

Captisol-Enabled, propylene glycol-free Melphalan is an intravenous formulation of melphalan being investigated for the multiple myeloma transplant setting, for which it was earlier granted an Orphan Drug Designation by the FDA.

Spectrum Pharma noted that the Phase 2 pivotal trial evaluating CE-Melphalan was a multi-center trial evaluating safety and efficacy. The primary objective of the study was to determine the overall safety and toxicity profile in multiple myeloma patients receiving 200 mg/m2 of CE-Melphalan as myeloablative therapy prior to autologous stem cell transplantation or ASCT.

The secondary objectives evaluated the efficacy of CE-Melphalan in this patient population, as measured by Multiple Myeloma Response Rate, and the rates of myeloablation and engraftment.

The primary as well as secondary endpoints of this Phase 2 trial were met, and a comprehensive NDA was submitted to the FDA, Spectrum Pharma noted.

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Spectrum Pharma Submits NDA For CE-Melphalan

Rudimentary egg and sperm cells made from stem cells

Southern Illinois University/Science photo Library

Some hope that sperm cells could one day be derived from the skin cells of a man who is otherwise sterile and that a similar process cold produce viable egg cells from a sterile woman's body.

Israeli and UK researchers have created human sperm and egg precursor cells in a dish, starting from a person's skin cells. The achievement is a small step towards a treatment for infertility, although one that could face significant controversy and regulatory hurdles.

The experiment, reported online in Cell on 24 December1, recreates in humans parts of a procedure first developed in mice, in which cells called induced pluripotent stem (iPS) cells reprogrammed cells that can differentiate into almost any cell type are used to create sperm or eggs that are subsequently manipulated to produce live births by in vitro fertilization.

In 2012, stem-cell biologist Mitinori Saitou of Kyoto University in Japan and his collaborators created the first artificial primordial germ cells (PGCs)2. These are specialized cells that emerge during embryonic development and later give rise to sperm or eggs. Saitou made them in a dish, starting with skin cells reprogrammed to an embryonic-like state through iPS-cell technology (see 'Stem cells: Egg engineers'). They also were able to achieve the same result starting with embryonic stem cells.

Although his cells could not develop beyond this precursor stage in the dish, Saito found that if he placed them in mouse testes, they would mature into sperm, and if he placed them in ovaries, they would mature into functional eggs. Both sperm and eggs could be used for in vitro fertilization.

Efforts to engineer similarly functional gametes in humans have produced PGC-like cells, but with such a low efficiency success rate of turning stem cells into gametes that it was difficult for others to expand on the work.. Previous efforts also required the introduction of genes that would render the cells unusable in the clinic.

Ewen Callaway reports on the ethical challenges of using lab-made sperm and egg cells in fertility treatments.

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Now a team led by Azim Surani of the University of Cambridge, UK, and Jacob Hanna of the Weizmann Institute of Science in Rehovot, Israel, has replicated the in vitro portion the first half, says Hanna of Saitous efforts in humans.

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Rudimentary egg and sperm cells made from stem cells