BBC – Future – Unjustified hype of stem cell therapies

Jay Shetty is 8 years old. He is intelligent and brilliant, says his mother Shilpa, even though he can not do everything his younger brother can do. "Jay does not sit down or use his hands a lot. He is nonverbal and we do not know how much he can see, "she says. "But he plays with us and tries to copy everything his younger brother Kairav ​​does."

Jay has cerebral palsy. In his early years, Shilpa was desperate to find something that could help him. While browsing the Internet late at night, she became aware of a stem cell trial at Duke University in North Carolina, but Jay was not eligible. When Kairav ​​was born in 2015, Shilpa and her husband stored the umbilical cord blood of their younger son, who was rich in blood stem cells, in the hope that another trial would come out. That was the case and this time, children with siblings cord blood could participate. Was she worried about the risks for Jay? "It was not invasive and he could not really hurt." To raise the £ 15,000 treatment bill, they have supplemented the funds already collected for private physiotherapy and hydrotherapy with a personal loan and a new fundraising campaign backed by the cordon. bank where Kairav's cord blood had been stored.

Cerebral palsy is a group of diseases that affect mobility and coordination throughout life. In Jay's case, says Shilpa, complications that occurred at the time of her birth led to the disease. Cerebral palsy is incurable, but physiotherapy, speech therapy, and occupational therapy can reduce some symptoms. Shilpa hoped, however, that Jay's stem cell therapy – a two-hour infusion into his veins – would bring benefits far beyond anything they had tried before.

We all have stem cells – they are constitutive cells, capable of developing into a wide range of specialized cell types, such as muscle, skin or brain cells. Stem cells not only rebuild our old cells, but also intervene to repair and replace injured tissue. As a result, they have been compared to our own army of microscopic doctors, but this army is relatively small.

The excitement of stem cell therapy revolves around the ability to produce more of these cells in the laboratory so that they can be used to produce new tissues, replace damaged cells and demystify the mechanisms of the disease.

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Until now, researchers have focused mainly on the development of two types of stem cells: embryonic stem cells and adult stem cells. Embryonic stem cells, extracted from a growing embryo, have the natural advantage of being able to give birth to any other cell in the body, called pluripotency attribute. Some people have however expressed ethical concerns about the use of embryos in the production of these stem cells – problems that are bypbaded by the use of stem cells obtained from adult tissues. Adult stem cells are not naturally pluripotent, which means that they tend to be more specialized and therefore can only develop in a narrower range of cell types. However, they can be reprogrammed to regain this flexibility of development.

Stem cell therapies are certainly very promising for some disorders. Proven and licensed stem cell therapies already exist for blood and immune conditions such as leukemia, lymphoma and myeloma. It is also approved in some countries for chemical eye burns.

Hopes of using stem cells to treat other disorders have inspired many new clinical trials and have led to a "stem cell tourism" focused on Ukraine, Panama and Thailand. By 2018, there were more than 432 US companies in 716 clinics engaged in the direct commercialization of stem cell processing by consumers.

These clinics share a common feature: exorbitant fees – and even trials like Duke University are very expensive.

This is where crowdfunding makes sense. A recent study published in the journal of the American Medical Association identified 408 US campaigns for stem cell treatment on YouCaring and GoFundMe, with over $ 7 million requested and 13,050 donors. Clinics often actively promote these campaigns: one at Northwestern Medicine has a manual with a section on "methods of solicitation".

Campaigns often minimize potential risks or omit them entirely:

"It's so simple and fast, with minimal side effects," says a page that tries to raise funds for a man with Parkinson's disease.

"More importantly, it has been shown that it slows the progression of the disease without any side effects," describes another, raising funds for a person with Amyotrophic Lateral Sclerosis (ALS) – a common form of motor neuron disease.

Only 26 of these 408 campaigns mentioned "risk" and even then as safe or low risk compared to alternative treatments.

It is understandable that activists minimize dangers – donors may not contribute otherwise. But these cases tell another story:

• In 2017, Doris Tyler, a 77-year-old former music teacher, raised funds on GoFundMe to cover stem cell therapy in Georgia, USA, to treat age-related macular degeneration ( AMD). "We love you, Doris!" Wrote a supporter. Before treatment, she was able to read books in large print and navigate home. Tyler is now almost blind: "When I wake up in the morning, one of the most difficult things is to open my eyes and see that everything is still black. And it will be like that until I go to bed. At least three other patients with AMD lost their sight following stem cell treatments in Florida in 2015.
• At least seventeen patients have been hospitalized in the United States in the past year after umbilical cord blood injections. The Centers for Disease Control have confirmed a series of bacterial infections. Most of these patients were treated in orthopedic, chiropractic and pain treatment clinics and received injections into the spine, knees and shoulders.
• Following a stroke in his early 60s, Jim Glbad applied for stem cell therapy in Argentina, China and Mexico (cost: $ 200,000). A tumor of the spinal cord paralyzed his right leg eventually (stroke had already paralyzed him to the left). The DNA badysis indicated that the tumor was born from the injected stem cells.
• A 9-year-old boy developed several tumors in the brain and spinal cord after a stem cell transplant. The pathological badysis confirmed that the tumor of the spine contained cells of at least two donors.

Where crowdfunding campaigns fail to refer to risk, this may be due to the fact that some clinics themselves hardly pbad it on. Paul Knoepfler, a biomedical scientist from the University of California Davis School of Medicine, attended a seminar on training in a clinic (used to recruit patients and promising significant discounts when registering ). Staff, mostly dressed in medical scrubs, neglected to mention potential adverse events badociated with stem cell transplants. The hearing, however, received a credit application form to complete. Knoepfler wrote that the experience was more like "attending a compelling entertainment show or something on a home shopping network than an educational seminar".

In addition to minimizing the risks of these therapies, crowdfunding campaigns sometimes overestimate the benefits.

"Stem cell therapy has helped thousands of autistic children," one of them said. The campaign, which aims to send a boy to Panama, has raised more than $ 18,000 since September, exceeding its target of $ 15,000.

"Patients with ALS have all said that it has done away with the damage done by ALS! Breathing improves, speech and swallowing improve. People in wheelchairs walked within two weeks, "said another. The campaign raised $ 1,040 from the patient's goal of $ 300,000 to date.

Yet many experts say that these claims are premature.

There is currently no evidence of the efficacy of stem cell therapy in the treatment of autism, as Alycia Halladay, scientific scientist at the Autism Science Foundation, wrote in Scientific American last year. Arnold Kriegstein, a professor of neurology at the University of California in San Francisco, similarly pointed out that recent autism tests using stem cell transplantation have failed to confirm its efficacy, although have claimed the opposite. He describes the research as "premature".

The use of stem cell-based treatments in ALS is particularly difficult. Even if the transplanted cells are able to migrate to the affected areas, they mature and integrate into the patient's nervous system before the disease reverts (life expectancy varies). but is on average two to five years from diagnosis), hostile environment with motor neurons dying around them. At the present time, most trials are rather focused on the use of stem cells to create laboratory models of motor neurons on which drugs can be tested and the pathological mechanisms studied. The MND Association believes that stem cell research is essential for understanding, preventing and treating MND, but states, "There is currently no reliable evidence to suggest that strains can be used as an effective treatment.

This study from the Journal of the American Medical Association revealed that 43.6% of campaigns involved definitive statements or some about the effectiveness of treatment. It is not too difficult to trace these exaggerated claims in clinics that use "marks of scientific legitimacy" – articles published in journals with little or no peer reviews, in addition to the implicit links with preclinical research in reputable but unaffiliated research centers.

Sometimes the media has helped spread unfounded hype. In 2014, former soldier James DeLittle, diagnosed with Parkinson's disease, paid £ 7,000 for a stem cell intervention in Ukraine. Then the press frequently cited the clinic's claim to improve 75% of their patients. "After only one of the two treatments, the doctor asked me to touch my nose with my eyes closed and I was on the spot – I could not believe it," DeLittle said in a statement. # 39; era. "My Parkinson's gives the impression of a spring that pulls me constantly to the left. But immediately after the treatment, the strength did not feel so strong and my balance was so much better. "

Two years later, a deteriorating DeLittle told the BBC that he was feeling "annoyed, out-of-pocket and damn". Yet, most of these 2014 readers will never know that the man who hoped that a stem cell-based treatment would be "a miracle in the making" eventually concluded that it was nothing more than more than a scam.

Patients may not even get the price for which they paid (not to mention giving up effective treatments). Lisa Fortier, a researcher in regenerative medicine at Cornell University, tested nine products, but "none contained stem cells or a single living cell of any type." Thus, people are potentially crowdfunding and donors are contributing to alleged stem cell-based treatments that do not contain stem cells.

Not all stem cells are created equally. Some trials use mesenchymal stem cells – cells in the bone marrow, for example, that play an important role in the manufacture and repair of skeletal tissues, such as cartilage, bone and adipocytes. But these are now serious questions about whether they work even as stem cells. Even the person who named them for the first time, Arnold Caplan, believes they should be renowned for suppressing the absolute hype about their potential: "I was wrong. I take back the name that I gave to these extremely important cells. "

None of these negates the potential of future (authentic) stem cell therapies to help some neurological diseases. Neurodegeneration in Parkinson's disease is relatively focal – dopaminergic neurons are progressively lost in a specific region called the middle brain – making it a good candidate for cell replacement of some of its symptoms. An essay from the Kyoto University uses induced pluripotent stem cells, developed by reprogramming the skin and other cells to return to an embryonic state. These become ready to transform into other types of cells, in this case, precursor cells of dopamine. "We pierced the front of the left side of the head and transplanted about 2.4 million cells," the researchers said excitedly about their first patient at the start of their two-year trial. Parkinson's UK remains optimistic about the potential of stem cell transplants, but insists that research must continue in the UK's "strong ethical and regulatory framework".

Greater interest has been focused around multiple sclerosis. Autologous hematopoietic stem cell transplantation (AHSCT) aims to replace or restart the body's immune system: high doses of chemotherapy destroy the patient's existing immune system, which is then reconstructed using its own stem cells collected before chemotherapy.

The AHSCT for multiple sclerosis is available in some private clinics in the UK and in the NHS, though in a very small number of centers with limited eligibility. The treatment is aggressive, still largely experimental worldwide and has an estimated mortality rate of 1 in 330.

Why, however, is stem cell therapy offered in this way for multiple sclerosis (MS) in the absence of similar approaches for other neurological conditions?

"In MS, the disease has a clear immune base. So it makes a lot more sense to do a bone marrow transplant as a way to treat the disease, "says Roger Barker, clinical neuroscientist at the University of Cambridge. "In neurodegenerative disorders [such as Parkinson’s]And yet, despite the reasonable promise of using stem cell transplants for the treatment of multiple sclerosis, many patients have been disappointed with the results – as recently announced Caroline Wyatt, of the BBC, in his quest to treat his own MS.

Some patients feel that they simply do not have the time to wait for sufficient evidence from long-term clinical trials. Respond to this funding request from a patient with ALS, a condition in which half of patients die within three years of their first symptoms:

"I breathe 32%, I can not talk or lose control of my hands and legs. I have a respirator 12 to 14 hours a day … PLEASE HELP! "

Does not the patient who has "32% less breathing" have the right to try something that could save him / her, crowdfunding even if this treatment is administered in an unregulated clinic? Barker is concerned that this vulnerability is being exploited, citing potential risks, including tumor formation.

But he also believes that legitimate research on stem cells will suffer. "In the event of a problem, regulators could prohibit such therapies, believing that these clinics offer essentially the same therapies as centers that have slowly progressed to clinical trials through appropriate rational approaches," says Barker.

Although regulators must play a role in parallel with cross-border partnerships, there is a growing consensus that crowdfunding platforms should also take their responsibilities. Campaigns for unsafe treatments or lack of evidence continue to generate millions of dollars.

Protect patients

It is true that these platforms can empower patients to explore options, hope and gaps in insurance, while allowing families and friends to expand their support. But should not they also ban bad actors and put an end to misinformation (campaigns are shared hundreds of thousands of times on social media)?

Not necessarily, suggested a GoFundMe statement to Gizmodo earlier this year: "While we hope to be a useful resource for personal fundraising, we believe it is not our responsibility to tell them what decision to make. After a call to crowdfunding sites to rigorously submit them The veterinarian calls to protect patients from untested or dangerous treatments (such as "ozonotherapy" and vitamin infusions), GoFundMe has banned users solicit donations for treatment at certain months of the clinic and indicates that they are actively badessing fears surrounding certain stem cell campaigns.

"With these new concerns raised by some stem cell clinics, we are taking a thoughtful approach to addressing stem cell campaigns while continuing to provide a safe and secure place for people to raise money for their needs and causes. We have contacted experts and medical regulatory authorities in the space to understand the latest regulatory developments and their impact on our customers, "they said in a statement.

JustGiving, who had similar concerns, previously said, "We do not think we have the expertise to make a decision." In an email to the BBC, they said they were ensuring that all pages crowdfunding complies with the legal requirements. to affirm that "the safety and well-being of people using our platform, whether it is to raise funds or to donate to a cause, is always our priority".

Tree of Hope, a UK crowdfunding organization and a children's charity, claim a different approach. Their medical committee takes advice on the UK Stem Cell Foundation's campaigns. "Families are turning to Tree of Hope when all other options have been exhausted," said Lee Vallins, deputy general manager and head of family support for the charity. "We work with incredible, though often desperate, parents, and we work with different options at their own pace." However, while they have encouraged a number of families to raise funds for stem cell transplantation, guarantees are in place.

"We easily spend time with parents who call us for advice on this type of therapy and we often decline a request if parents do not want to consider recognized clinical trials or alternative treatment options," says Vallins. "Although we are not one of the largest crowdfunding organizations, we certainly strive to be one of the most ethical through our controls and measurements throughout the process."

Hunting for hope

Jay Shetty finally received a two-hour stem cell infusion into a cannula at his arm at Duke University. What were Shilpa's expectations? "I knew it was not a cure, I knew he was not going out by walking and running. But I thought at least that Jay would be able to sit in six months, to be honest. Unfortunately, that did not happen, "she says. "We have not seen any dramatic changes, but he is not so spastic, he is more aware, for us, a family, we think he is big enough. It is a kind of foundation for all physiotherapy. "

But was stem cell therapy responsible for this improvement? Maybe Jay would have gained more skills growing up? "It's hard to pin down because we've been in therapy for a long time," says Shilpa.

To date, stem cell studies on cerebral palsy at the Duke University Medical Center under the direction of Joanne Kurtzberg have not yet met expectations although work is continuing. In 2017, 63 children with cerebral palsy were randomized to receive treatment (single infusion of cord blood) or placebo. Disappointingly, the researchers found no change in the primary endpoint of the trial: motor function one year after the initial infusion. They reported better results at higher doses (highlighted in some media), but Paul Knoefler of UC Davis School of Medicine is not convinced. "Based on the small size of the study, the high degree of variability in samples from the same groups, changes in the placebo group compared to expectations, and the modest nature of the possible differences with the higher dose by compared to placebo, I am convinced. not convinced that the reported effect was significant, "he says. He also tells me that with a study by the Duke group on autism, these results "do not suggest a strongly positive effect of umbilical cord cells in the neurological conditions of the child."

Cells4Life, the cord blood stem cell bank that supported Jay's fundraising, says on his website that "Duke's trials have shown that cord blood can reverse the symptoms of cerebral palsy." (Cells4Life states that its mission is to "store the cord blood of every baby." Their price ranges from £ 1,495 to £ 2,090, with additional annual storage fees.)

Shettys are not discouraged. "If we find a match and Duke opens a similar case, I'd be happy to pay for it," says Shilpa. "If we have money, we will continue to do it again and again to be honest. In Jay's case, there are a lot of empty spaces in his brain and he needs new cells. "

Meanwhile, she and the other parents will continue to browse the Internet late at night. Anything that could help their children could be helpful, looking for hope and seeking treatment. As long as they do, stem cell clinics promise to answer their call.

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Jules Montague is a writer and neurologist in London. His first book, Lost and Found, explores what remains of the person when his wits disappear – from dementia and brain damage to sleep disorders and multiple personality disorders. His second book, The Diagnosis Cure, will be published next year and explores how the medical diagnosis is profoundly altered by the forces of trade, imperialism and gender discrimination.

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