Stem Cell Clinic

Novel stem cell-derived model created of inflammatory neurological disorder – Medical Xpress

August 10, 2017 Organoids are clusters of cultured cells self-organized into miniature replicas of organs. In this image, neural progenitor cells (NPCs) are green. As the brain organoids increase in size, multi-layer structures composed of NPCs develop with intermediate progenitors (not shown) and cortical layer neurons (red). Cell nuclei are depicted in blue. Credit: Cleber A. Trujillo, UC San Diego

An international team of scientists, led by University of California San Diego School of Medicine researchers, has created a human stem cell-based model of a rare, but devastating, inherited neurological autoimmune condition called Aicardi-Goutieres Syndrome (AGS). In doing so, the team was able to identify unusual and surprising underlying genetic mechanisms that drive AGS and test strategies to inhibit the condition using existing drugs.

Two repurposed FDA-approved drugs showed measurable effect, rescuing cells from the effects of AGS. The findings point to the promise of future clinical trials and to the utility of creating novel stem cell-based models of human diseases when no other models are available.

The findings are published in the August 10 online issue of Cell Stem Cell.

"Our approach can now be used to investigate other neurological conditions, like autism and schizophrenia and overlapping autoimmune disorders that dysfunction in similar ways," said Alysson Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine.

First described in 1984, AGS typically involves early-onset inflammation affecting the brain, immune system and skin. Its severity depends upon which genes are involvedthere are six typesbut usually results in pronounced physiological and psychological consequences, from microcephaly (an abnormally small head) and spasticity to skin and vision problems and joint stiffness, all appearing in the first year of life. The syndrome is progressive, resulting in death or a persistent vegetative state in early childhood. Currently, there is no cure; the only treatments are symptomatic or palliative.

The clinical features of AGS mimic those of viral infections acquired in utero, before birth, with increased levels of inflammatory markers and other signatures of inflammatory response. However, Muotri said there is no link between AGS and exogenous pathogens. Previous research has shown that AGS patients have mutations in genes critical to nucleic acid metabolism in the regulation of cellular immune response, among them a deficiency in an enzyme called TREX1, which helps prevent abnormal DNA from accumulating in cells.

Deeper probing into the pathogenesis of AGS has been difficult because animal models do not accurately mimic the human version of the disease. So Muotri, with colleagues, used embryonic stem cells and induced pluripotent stem cells (iPSCs) derived from AGS patients to create six cellular models of the condition. In the past, Muotri's lab has developed similar "disease-in-a-dish" neuronal models of autism, anorexia nervosa and Williams Syndrome, among other rare genetic neurological conditions.

From the iPSCs, they also created cerebral organoids or "mini-brains"larger clusters of neurons that organize themselves into a cortical structure, similar to a developing human cerebral cortex.

The researchers found that with TREX1 not functioning normally, all of the cell models displayed excess extra-chromosomal DNA and that a major source of the excess DNA came from LINE1 (L1) retroelements. L1s are repetitive sequences of DNA with the ability to autonomously copy-and-paste themselves within the human genome. In the past, they have been called "jumping genes" and, because their function within cells is largely unknown, "junk DNA."

However the term "junk DNA" is increasingly becoming a misnomer. In work published in 2005, for example, Muotri and colleagues reported that L1s have a high impact on brain cells compared to other tissues, suggesting an important, if so far mysterious, role in brain development.

Since then, he said, researchers around the world have investigated the role of L1s in creating a genetic mosaicism in the brain. "These are ancient, genomic parasites that replicate inside our cells. The majority of the current work is focusing on the impact of this genome mosaicism, but we decided to also look outside of the nucleus. And what we found was a big surprise."

In some of the AGS cell models created by the researchers, toxins from excess DNA built up. Others showed an abnormal immune response, secreting toxins that induced cell death in other cells. The combined effect in organoids was a massive reduction in neuron growth when the opposite should occur. "These models seemed to mirror the development and progression of AGS in a developing fetus," said Muotri. "It was cell death and reduction when neural development should be rising."

The cell death was trigged by the anti-viral response from the L1 molecules outside the nucleus. "We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment," said Charles Thomas, a former graduate student in the Muotri lab and first author of the study. "This mechanism seems human-specific. We don't see this in the mouse."

The researchers observed that AGS pathogenesis was similar to a retroviral infection and wondered whether existing HIV antiretroviral drugs might be effective in interfering in L1 replication. Two drugs were tested in the cell models: Stavudine and Lamivudine. Both drugs resulted in reduced L1 and cell toxicity. Cell model growth returned in all cell types and in the complex, differentiated colonies of nerve cells that comprise organoids.

The data supported the idea that HIV drugs could benefit AGS patients, Muotri said. A clinical trial led by study co-author Yanick Crow, MRCP, PhD, at Sorbonne Paris Cite University and the University of Manchester, has already started in Europe.

Muotri said the findings were illuminating and encouraging, providing a platform and impetus for further study of the pathology of neuroinflammation and drug discovery. "It's important to note that while this work focused on AGS, nerve cells in schizophrenia show an overabundance of L1 elementsand there is an overlap with other autoimmune disorders.

"This is a great example of how a fundamental basic research could be rapidly translated into clinics. Are there analogous mechanisms at work in these different diseases? Is this modeling strategy relevant for better understanding and treating them? These are questions we will now pursue."

Explore further: Researchers create model of anorexia nervosa using stem cells

More information: Charles A. Thomas et al, Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation, Cell Stem Cell (2017). DOI: 10.1016/j.stem.2017.07.009

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Novel stem cell-derived model created of inflammatory neurological disorder - Medical Xpress

Test results after stem cell transplant for multiple myeloma can … – Medical Xpress

August 10, 2017 Dr. Gurmukh Singh, vice chair of clinical affairs for the Department of Pathology and Walter L. Shepeard Chair in Clinical Pathology at the Medical College of Georgia at Augusta University. Credit: Phil Jones

It's a cancer of the plasma cells, which normally make an array of antibodies that protect us from infection.

With multiple myeloma, the cells start primarily producing instead a singular product, called a monoclonal antibody, or M spike, that leaves patients vulnerable for serious infections, like pneumonia, and can even eat away at their bones.

Sophisticated laboratory tests used to both diagnose the disease then follow treatment response, can send confusing messages to patients and their physicians, particularly after stem cell therapy to try to restore a healthy antibody mix, says Dr. Gurmukh Singh. Singh, vice chair of clinical affairs for the Department of Pathology and Walter L. Shepeard Chair in Clinical Pathology at the Medical College of Georgia at Augusta University, is corresponding author of the study highlighting reasons for potential confusion in the Journal of Clinical Medicine Research.

The tests, serum protein electrophoresis and serum immunofixation electrophoresis, or SPEP/SIFE, and serum free light chain assay, or SFLCA, separate proteins into groups according to their electrical charge.

The M spike stands out as a distinctive, dense band of color among the layers of protein groups, while typical antibody levels create bands of lighter smears.

But after stem cell therapy, which first destroys cancerous plasma cells then restores healthy ones, follow up profiles often yield a lineup of antibodiescalled an oligoclonal patternthat can look eerily similar to the M spike.

The confusion comes because there again may be a prominent and likely short-lived band of proteins that emerges as the antibody mix begins, ideally, to normalize.

"We want to emphasize that oligoclonal bands should mostly be recognized as a response to treatment and not be mistaken as a recurrence of the original tumor," Singh says.

The key clarifier appears to be the location of the malignant, monoclonal spike when the diagnosis is made compared to the location of new spikes that may show up after stem cell therapy in these oligoclonal bands, says Singh.

"If the original peak was at location A, now the peak is location B, that allows us to determine that it is not the same abnormal, malignant antibody," Singh says, pointing toward different before and after treatment profiles on a patient.

Normally antibodies spread out in a usual sequence in these studies. "If it's in a different location, it's not the same protein," reiterates Singh. "If the location is different, this is just a normal response of recovery of the bone marrow that could be mistaken for recurrence of the disease," Singh says of the oligoclonal bands that can also temporarily show up in response to an infection.

He notes while the prominent bands are typically short-lived following treatment, the recognition that they are non-malignant may occur only in retrospect.

For the study, Singh and his team looked at lab and clinical data on 251 patients with multiple myeloma treated from January 2010 to December 2016; 159 of those patients received autologous stem cell transplants. Each patient had at least three tests, and at least two of the tests were following their transplant.

They found the incidence of oligoclonal patterns was significantly higher in patients who had a stem cell transplant than the patients who had chemotherapy alone: 57.9 percent compared to 8.8 percent. Only five of the 159 patients who received a transplant had an oligoclonal pattern before treatment but 92 had one afterward. More than half of the the oligoconal patterns developed within the first year following a transplant. The earliest pattern was detected at two months - as soon as the first post-transplant tests were doneand a few occurred as long as five years later.

Autologous stem cell therapy is not considered curative for most patients with multiple myeloma. There is no clear cause of the disease but the risk does increase at age 40, Singh says.

Explore further: Excessive tests don't benefit patient, do increase cost in age-related immune disorder

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Test results after stem cell transplant for multiple myeloma can ... - Medical Xpress

Are Stem Cell Companies Abusing ClinicalTrials.gov? – PLoS Blogs (blog)

Im often asked about the safety of treatments that purport to inject stem cells into painful body parts. The reputation of stem cells seems to exceed the reach, with companies touting treatments that arent FDA approved or even being tested.

Back in March, an alarming article in the New England Journal of Medicinedescribed three women blinded by stem cell treatments two of the patients reported seeing a reference on the company website to registration at the National Institutes of Healths well-respected ClinicalTrials.gov, and assuming it applied to their treatment. It didnt.

In what is perhaps a modern version of hawking snake oil, companies can indeed register certain clinical trials without breaking any rules but desperate patients might not know that.

There is no doubt that some patients have misinterpreted a studys listing on ClinicalTrials.gov as a stamp of legitimacy, federal review, and compliance. In this way, treatments with no safety or efficacy data, no prior clinical study, and no ongoing clinical trials under FDA review, appear to have federal approval. Such a misunderstanding can lead to disastrous outcomes for patients, said Thomas Albini, MD, of the Bascom Palmer Eye Institute of the University of Miami, who treated the blinded women.

When I wrote about the disaster here at DNA Scienceand atMedscape Medical News, my Medscape editor asked me to take a closer look at criteria for listing investigations at ClinicalTrials.gov. It proved an interesting exercise, but I declined to write an article, fearing lawsuits if I named companies.

ClinicalTrials.gov is where research groups, in academia and pharma/biotech, describe protocols to evaluate the safety and efficacy of new drugs, biologics, and devices, which FDA regulates, typically in randomized, controlled trials. But for an observational study that just follows what happens after a treatment, no such thumbs-up is required; no investigational new drug (IND) designation or investigational device exemption (IDE) need be filed. And that creates a loophole that companies are happily jumping through and luring patients in pain, who may know little about clinical trial design, and perhaps trust too much the companies and the doctors offering these services.

Its easy to see how people are fooled. One company claims that By providing access to registered clinical studies through the NIH, we are providing patients with the ability to choose a stem cell treatment center with the highest standard of care. If the treatment is experimental, how can there even be a standard of care?

MOST STUDIES LEGIT

I love ClinicalTrials.gov its packed with information about all manner of conditions, with contacts and references. I started my investigation by searching for studies that sounded bogus.

I began with a treatment that epitomizes pseudoscience: magnets. But I was fooled. Other than legit uses in medical devices, my magnet search called up as an acronym of sorts for theMothers and Girls Dancing Together Trial, a well-designed study on preventing childhood obesity, with a decent sample size and controls.

I also thought the randomised crossover trial of the acute effects of a deep-fried Mars bar or porridge on the cerebral vasculature was fake, but it turned out to be a medical students project, well done, and published in the Scottish Medical Journal.

But trial NCT02833532, sponsored by a Korean pharmaceutical company, was likely a joke, with the stated purpose of temporary penile enhancement and one of the investigators first name being Dong. Participants must answer the question How do you rate your penile size? Very small/small/normal/big/very big to enroll. Those accepted get to try something made of hyaluronic acid, which is found, coincidentally, in cocks combs.

Searching ClinicalTrials.gov for stem cells returns more than 4,000 entries, so I gave up. Fortunately, Leigh Turner, PhD, associate professor at the Center for Bioethics at the University of Minnesota, wasnt afraid of lawyers and took a more measured, scholarly approach. He recently published the intriguing findings in Regenerative Medicine, where you can find nice tables naming the stem cell companies that use and possibly abuse ClinicalTrials.gov.

AN ACADEMIC INVESTIGATION

Dr. Turner searched ClinicalTrials.gov for stem cells along with patient-sponsored, patient-funded, and self-funded because expecting patients to pay is a red flag. Only a very few real clinical trials charge patients, and those that do must have FDA approval to do so.

He found 7 such pay-as-you-go clinical trials, each enrolling more than 100 people, at the government website, and another 11 in a database of companies that provide direct-to-consumer stem-cell-based treatments. The DTC label indicates that the treatments arent part of a real experimental protocol. One of themhad signed up more than 3,000 gullible people.

The companies that charge patients yet proclaim a ClinicalTrials.gov listing are having their proverbial cake and eating it too borrowing the governmental veneer of a sanctioned clinical trial, while collecting fees. And many health care consumers arent even aware theyre being bamboozled.

Another red flag in a stem cell pitch is an everything-but-the-kitchen-sink list of targets. Stem Cell Network, for example, claims to be able to treat, using stem cells grown from a patients fat, some 28 conditions, including the vague knee problems, and also muscular dystrophy, ankle problems, neuropathy, asthma, and alopecia areata. Also be wary of stem cells derived from one body part like butt fat being injected into another body part such as eyeballs.

Wed like people to protect themselves by going to a reliable website, like ClinicalTrials.gov, to distinguish legitimate from bogus claims of stem cell clinics. But the findings of this paper challenge that advice because this valuable resource, which is designed to promote transparency and to help people find clinical trials, lists unlicensed and unproven stem cell interventions that companies turn into personal marketing platforms. So if you have ALS, MS, Parkinsons disease, a ClinicalTrials.gov listing looks like any other study on the NIH website. Many people think a listing is credible, Dr. Turner told me.

There is an urgent need for careful screening of clinical studies before they are registered with ClinicalTrials.gov, Dr. Turners paper concludes. But in the current climate of a nuclear threat, a health care system in disarray, and possible cuts to the CDC, FDA, and NIH, ramping up scrutiny at ClinicalTrials.gov is unlikely to have priority, if the President even has a clue what it is.

Its not possible to slash, burn, defund, and deregulate at every turn and think that federal agencies are going to improve how they function. But no administration is forever, no budget is forever, deregulatory moments dont last forever, and perhaps problems that are ignored or neglected now will be addressed in the future, with collateral damage along the way while nothing is done, warns Dr. Turner, who lives in Canada. I wonder if he has a spare room.

Those seeking stem cell treatments should check out the International Society for Stem Cell Research (ISSCR) Patient Handbook on Stem Cell Therapiesand stemcells.nih.gov. Alas, much of the media is still somewhat unfamiliar with the biology of stem cells, that they are not cells that can turn into any cell typebut that they self-renew and jettison a new stem cell at every division. Thats what makes them stem cells, not the ability to spawn specialized cells.

So I tell people who ask me if they should have stem cells shot into their aching knees or backs to do so only if they wouldnt object to an abnormal growth cancer forming there.

When it comes to stem cell therapies, its caveat emptor buyer beware!

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Are Stem Cell Companies Abusing ClinicalTrials.gov? - PLoS Blogs (blog)