Mixed Matches: How Your Heritage Can Save a Life

Today we bring you a guest blog from Athena Mari Asklipiadis. She’s the founder of Mixed Marrow, which is an organization dedicated to finding bone marrow and blood cell donors to patients of multiethnic descent. Athena helped produce a 2016 documentary film called Mixed Match that encourages mixed race and minority donors to register as adult donors.

Athena Asklipiadis

Due to the lack of diversity on the national and world bone marrow donor registries, Mixed Marrow was started in 2009 to increase the numbers of mixed race donors.

Prior to Mixed Marrow starting, other ethnic recruiters like Asians for Miracle Marrow Matches (A3M), based in Los Angeles, CA and Asian American Donor Program (AADP), based in Alameda, CA had been raising awareness in the Asian and minority communities for decades.  Closing the racial gap on the registry was something I was very much interested in helping them with so I began my outreach on the most familiar medium I knew—social media.

Because matching relies heavily on similar inherited genetic markers, I was particularly astonished seeing the less than 3% (back in 2009) sliver of the ethnic pie that mixed race donors made up.  Caucasians made up for about 70% at the time, with all minorities making up for the difference.  The ethnic breakdown made sense when comparing against actual population numbers, but a larger pool of minority donors was definitely something needed especially when multiracial people were being reported as the fastest growing demographic in the US.  Odds were just not in the favor of non-white searching patients.

Current Be The Match ethnic breakdown as of 2016.

After getting to know a local mixed race searching patient, Krissy Kobata, and hearing of her struggles finding a match, I knew I had to do my best to reach out to fellow multiracial people, most of which were young and likely online.  At the time, I was engaged with fellow hapas (half in Hawaiian Pidgin, referring mixed heritage) and mixed people via multiracial community Facebook groups and other internet forums.  One common thing I noticed, unlike topics like identity, food and culture– health was definitely not widely talked about. So with that lack of awareness, Mixed Marrow began as a facebook page and later as a website.  With the help of organizations like A3M supplying Be The Match testing kits, Mixed Marrow was able to also exist outside of the virtual world by hosting donor recruitment drives at different cultural and college events.

Athena Asklipiadis, Krissy Kobata and Mixed Match director, Jeff Chiba Stearns

After about a year of advocacy, in 2010, I connected with filmmaker Jeff Chiba Stearns to pitch an idea for a documentary on the patients I worked with.  Telling their stories in words and on flyers was not effective enough for me, I felt that more people would be inclined to register as a donor if they got to know the patients as well as I did.  Thus, the film Mixed Match was born.

Still from Mixed Match, Imani (center) and parents, Darrick and Tammy.

Still from Mixed Match, Imani mother, Tammy.

Over the course of the next 6 years, Jeff and I went on a journey across the US to gather not only patient stories, but input from pioneers in stem cell transplantation like Dr. Paul Terasaki and Dr. John E. Wagner.  It was so important to share these transplant tales while being as accurate and informed as possible.

Still from Mixed Match – Dr. Paul Teriyaki.

Our goal was to educate audiences and present a call-to-action where everyone can learn how they can save a life. Mixed Match not only highlights bone marrow and peripheral blood stem cell (PBSC) donation, but it also shares the possibilities of umbilical cord stem cells.

Mixed Match director, Jeff Chiba Stearns decided a great way to explain stem cell science and matching was through animation.  Stearns, with the help of animator, Kaho Yoshida, was able to reach across to non-medical expert audiences and create digestible and engaging imagery to teach what is usually very complex science.

Animation Still from Mixed Match.

At every screening we also make sure to host a bone marrow registry drive so audiences have the opportunity to sign up.  We have partnered with both the US national registry, Be The Match and Canadian Blood Services’ One Match registry.

Bone marrow drive at a Mixed Match screening in Toronto.

Nearly 8 years and about 40 cities later, Mixed Marrow has managed to spread advocacy for the need for more mixed race donors all over the US and even other countries like Canada, Japan, Korea and Austria all the while being completely volunteer-run.  It is our hope that through social media and film, Mixed Match, we can help share these important stories and save lives.

Further Information

Three people left blind by Florida clinic’s unproven stem cell therapy

Unproven treatment

Unproven stem cell treatments endanger patients: Photo courtesy Healthline

The report makes for chilling reading. Three women, all suffering from macular degeneration – the leading cause of vision loss in the US – went to a Florida clinic hoping that a stem cell therapy would save their eyesight. Instead, it caused all three to go blind.

The study, in the latest issue of the New England Journal of Medicine, is a warning to all patients about the dangers of getting unproven, unapproved stem cell therapies.

In this case, the clinic took fat and blood from the patient, put the samples through a centrifuge to concentrate the stem cells, mixed them together and then injected them into the back of the woman’s eyes. In each case they injected this mixture into both eyes.

Irreparable harm

Within days the women, who ranged in age from 72 to 88, began to experience severe side effects including bleeding in the eye, detached retinas, and vision loss. The women got expert treatment at specialist eye centers to try and undo the damage done by the clinic, but it was too late. They are now blind with little hope for regaining their eyesight.

In a news release Thomas Alibini, one of the lead authors of the study, says clinics like this prey on vulnerable people:

“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous.”

Warning signs

So what went wrong? The researchers say this clinic’s approach raised a number of “red flags”:

  • First there is almost no evidence that the fat/blood stem cell combination the clinic used could help repair the photoreceptor cells in the eye that are attacked in macular degeneration.
  • The clinic charged the women $5,000 for the procedure. Usually in FDA-approved trials the clinical trial sponsor will cover the cost of the therapy being tested.
  • Both eyes were injected at the same time. Most clinical trials would only treat one eye at a time and allow up to 30 days between patients to ensure the approach was safe.
  • Even though the treatment was listed on the clinicaltrials.gov website there is no evidence that this was part of a clinical trial, and certainly not one approved by the Food and Drug Administration (FDA) which regulates stem cell therapies.

As CIRM’s Abla Creasey told the San Francisco Chronicle’s Erin Allday, there is little evidence these fat stem cells are effective, or even safe, for eye conditions.

“There’s no doubt there are some stem cells in fat. As to whether they are the right cells to be put into the eye, that’s a different question. The misuse of stem cells in the wrong locations, using the wrong stem cells, is going to lead to bad outcomes.”

The study points out that not all projects listed on the Clinicaltrials.gov site are checked to make sure they are scientifically sound and have done the preclinical testing needed to reduce the likelihood they may endanger patients.

goldberg-jeffrey

Jeffrey Goldberg

Jeffrey Goldberg, a professor of Ophthalmology at Stanford and the co-author of the study, says this is a warning to all patients considering unproven stem cell therapies:

“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research.”

There are a number of resources available to people considering being part of a clinical trial including CIRM’s “So You Want to Participate in a Clinical Trial”  and the  website A Closer Look at Stem Cells , which is sponsored by the International Society for Stem Cell Research (ISSCR).

CIRM is currently funding two clinical trials aimed at helping people with vision loss. One is Dr. Mark Humayun’s research on macular degeneration – the same disease these women had – and the other is Dr. Henry Klassen’s research into retinitis pigmentosa. Both these projects have been approved by the FDA showing they have done all the testing required to try and ensure they are safe in people.

In the past this blog has been a vocal critic of the FDA and the lengthy and cumbersome approval process for stem cell clinical trials. We have, and still do, advocate for a more efficient process. But this study is a powerful reminder that we need safeguards to protect patients, that any therapy being tested in people needs to have undergone rigorous testing to reduce the likelihood it may endanger them.

These three women paid $5,000 for their treatment. But the final cost was far greater. We never want to see that happen to anyone ever again.

A horse, stem cells and an inspiring comeback story that may revolutionize tendon repair

Everyone loves a good comeback story. Probably because it leaves us feeling inspired and full of hope. But the comeback story about a horse named Dream Alliance may do more than that: his experience promises to help people with Achilles tendon injuries get fully healed and back on their feet more quickly.

Dream Alliance

Dream Alliance was bred and raised in a very poor Welsh town in the United Kingdom. One of the villagers had the dream of owning a thoroughbred racehorse. She convinced a group of her fellow townsfolk to pitch in $15 dollars a week to cover the costs of training the horse. Despite his lowly origins, Dream Alliance won his fourth race ever and his future looked bright. But during a race in 2008, one of his back hoofs cut a tendon in his front leg. The seemingly career-ending injury was so severe that the horse was nearly euthanized.

It works in horses, how about humans?
Instead, he received a novel stem cell procedure which healed the tendon and, incredibly, the thoroughbred went on to win the Welsh Grand National race 15 months later – one of the biggest races in the UK that is almost 4 miles long and involves jumping 22 fences. Researchers at the Royal Veterinary College in Liverpool developed the method and data gathered from the treatment of 1500 horses with this stem cell therapy show a 50% decrease in re-injury of the tendon.

It’s been so successful in horses that researchers at the University College of London and the Royal National Orthopaedic Hospital are currently running a clinical trial to test the procedure in humans.  Over the weekend, the Daily Mail ran a news story about the clinical trial. In it, team lead Andrew Goldberg explained how they got the human trial off the ground:

“Tendon injuries in horses are identical to those in humans, and using this evidence [from the 1500 treated horses] we were able to persuade the regulators to allow us to launch a small safety study in humans.”

Tendon repair: there’s got to be another way

Achilles tendon connects the calf muscle to the heel bone

The Achilles tendon is the largest tendon in the body and connects the calf muscle to the heel bone. It takes on a lot of strain during running and jumping so it’s a well-known injury to professional and recreational athletes but injuries also occur in those with a sedentary lifestyle. Altogether Achilles tendon injury occurs in about 5-10 people per 100,000. And about 25%-45% of those injuries require surgery which involves many months of crutches and it doesn’t always work. That’s why this stem cell approach is sorely needed.

The procedure is pretty straight forward as far as stem cell therapies go. Bone marrow from the patient’s hip is collected and mesenchymal stem cells – making up a small fraction of the marrow – are isolated. The stem cells are transferred to petri dishes and allowed to divide until there are several million cells. Then they are injected directly into the injured tendon.

A reason to be cautiously optimistic
Early results from the clinical trial are encouraging with a couple of the patients experiencing improvements. The Daily Mail article featured the clinical trial’s first patient who went from a very active lifestyle to one of excruciating ankle pain due to a gradually deteriorating Achilles tendon. Though hesitant when she first learned about the trial, the 46-year-old ultimately figured that the benefits outweighed the risk. That turned out to be a good decision:

“I worried, because no one had ever had it before, except a horse. But I was more worried I’d end up in a wheelchair. The difference now is amazing. I can do five miles on the treadmill without pain, and take my dog Honey on long walks again.”

The researchers aren’t exactly sure how the therapy works but mesenchymal stem cells are known to release factors that promote regeneration and reduce inflammation. The first patient’s positive results are just anecdotal at this point. The clinical trial is still recruiting volunteers so definitive results are still on the horizon. And even if that small trial is successful, larger clinical trials will be required to confirm effectiveness and safety. It will take time but without the careful gathering of this data, doctors and patients will remain in the dark about their chances for success with this stem cell treatment.

Hopefully the treatment proves to be successful and ushers in a golden era of comeback stories. Not just for star athletes eager to get back on the field but also for the average person whose career, good health and quality of life depends on their mobility.

Building the World’s Largest iPSC Repository: An Interview with CIRM’s Stephen Lin

This blog originally appeared on RegMedNet and was provided by Freya Leask, Editor & Community Manager of RegMedNet. In this interview, Stephen Lin, Senior Science Officer at the California Institute Regenerative Medicine (CIRM), discusses the scope, challenges and potential of CIRM’s iPSC Initiative. 

 

Stephen Lin

Stephen Lin received his PhD from Washington University (MO, USA) and completed his postdoctoral work at Harvard University (MA, USA). Lin is a senior science officer at CIRM which he joined in 2015 to oversee the development of a $32 million repository of iPSCs generated from up to 3000 healthy and diseased individuals and covering both complex and rare diseases. He also oversees a $40 million initiative to apply genomics and bioinformatics approaches to stem cell research and development of therapies. Lin is the program lead on the CIRM Translating Center which focuses on supporting the process development, safety/toxicity studies and manufacturing of stem cell therapy candidates to prepare them for clinical trials. He was previously a scientist at StemCells, Inc (CA, USA) and a staff scientist team lead at Thermo Fisher Scientific (MA, USA).

Q: Please introduce yourself and your institution.

I completed my PhD at Washington University in biochemistry, studying the mechanisms of aging, before doing my postdoc at Harvard, investigating programmed cell death. After that, I went into industry and have been working with stem cells ever since.

I was at the biotech company StemCells, Inc for 6 years where I worked on cell therapeutics. I then joined what was Life Technologies which is now Thermo Fisher Scientific.  I joined CIRM in 2015 as they were launching two new initiatives, the iPSC repository and the genomics initiative, which were a natural combination of my experience in both the stem cells industry and in genetic analysis.  I’ve been here for a year and a half, overseeing both initiatives as well as the CIRM Translating Center.

Q: What prompted the development of the iPSC repository?

Making iPSCs is challenging! It isn’t trivial for many research labs to produce these materials, especially for a wide variety of diseases; hence, the iPSC repository was set up in 2013. In its promotion of stem cells, CIRM had the financial resources to develop a bank for researchers and build up a critical mass of lines to save researchers the trouble of recruiting the patients, getting the consents, making and quality controlling the cells. CIRM wanted to cut that out and bring the resources straight to the research community.

Q: What are the challenges of storage so many iPSCs?

Many of the challenges of storing iPSCs and ensuring their quality are overcome with adequate quality controls at the production step. The main challenge is that we’re collecting samples from up to 3000 donors – the logistics of processing that many tissue samples from 11 funded and nonfunded collectors are difficult. The lines are being produced in the same uniform manner by one agency, Cellular Dynamics International (WI, USA), to ensure quality in terms of pluripotency, karyotyping and sterility testing.

Once the lines are made, they are stored at the Coriell Institute (NJ, USA). During storage, there is a challenge in simply keeping track of and distributing that many samples; we will have approximately 40 vials for each of the 3000 main lines. Both Cellular Dynamics and Coriell have sophisticated tracking systems and Coriell have set up a public catalog website where anyone can go to read about and order the lines. Most collections don’t have this functionality, as the IT infrastructure required for searching and displaying the lines along with clinical information, the ordering process, material transfer agreements and, for commercial uses, the licensing agreements was very complex.

Q: Can anyone use the repository?

Yes, they can! There is a fee to utilize the lines but we encourage researchers anywhere in the world to order them. The lines are mostly for research and academic purposes but the collection was built to be commercialized, all the way from collecting the samples. When the samples were collected, the patient consent included, among other things, banking, distribution, genetic characterization and commercialization.

The lines also have pre-negotiated licensing agreements with iPS Academia Japan (Kyoto, Japan) and the Wisconsin Alumni Research Foundation (WI, USA). Commercial entities that want to use the cells for drug screening can obtain a license which allows them to use these lines for drug discovery and drug screening purposes without fear of back payment royalties down the road. People often forget during drug screening that the intellectual property to make the iPSCs is still under patent, so if you do discover a drug using iPSCs without taking care of these licensing agreements, your discovery could be liable to ownership by that original intellectual property holder.

Q: Will wider access to high quality iPSCs accelerate discovery?

That’s our hope. When people make iPSCs, the quality can be highly variable depending on the lab’s background and experience, which was another impetus to create the repository. Cellular Dynamics have set up a very robust system to create these lines in a rigorous quality control pipeline to guarantee that these lines are pluripotent and genetically stable.

Q: What diseases could these lines be used to study and treat?

We collected samples from patients with many different diseases – from neurodevelopmental disorders including epilepsy and neurodegenerative diseases such as Alzheimer’s, to eye disease and diabetes – as well as the corresponding controls. We also have lines from rare diseases, where the communities have no other tools to study them, for example, ADCY5 related dyskinesia. You can read our recent blogs about our efforts to generate new iPSC lines for ADCY5 and other rare diseases here and here.

Q: What are your plans for the iPSC initiative this year?

We’re currently the largest publicly available repository in the world and we aren’t complete yet. We have just under half of the lines in with the other half still being produced and quality controlled. Something else we want to do is add further information to make the lines more valuable and ensure the drug models are constantly improving. The reason people will want to use iPSCs for human disease modeling is whether they have valuable information associated with them.  For example, we are trying to add genetic and sequencing information to the catalog for lines that have it. This will also allow researchers to prescreen the lines they are interested in to match the diseases and drugs they are studying.

Q: Does the future for iPSCs lie in being utilized as tools to find therapeutics as opposed to therapeutics themselves?

I think the future is two pronged. There is certainly a future for disease modeling and drug screening. There is currently an initiative within the FDA, the CiPA initiative, is designed to replace current paradigms for drug safety testing with computational model and stem cell models. In particular, they hope to be able to screen drugs for cardiotoxicity in stem cells before they go to patients.  Mouse and rodent models have different receptors and ion channels so these cardiotoxic effects aren’t usually seen until clinical trials.

The other avenue is in therapeutics. However, this will come later in the game because the lines being used for research often can’t be used for therapeutics. Patient consent for therapeutic use has to be obtained at sample collection, the tissue should be handled in compliance with good lab practice and the lines must be produced following good manufacturing process (GMP) guidelines. They must then be characterized to ensure they have met all safety protocols for iPSC therapeutics.

There is already a second trial being initiated in Japan of an iPSC therapeutic to treat macular degeneration, utilizing allogenic lines that are human leukocyte antigen-compatible and extensively safety profiled. Companies such as Lonza (Basel, Switzerland) and Cellular Dynamics are starting to produce their own GMP lines, and CIRM is funding some translation programs where clinical grade iPSCs are being produced for therapeutics.


Further Reading

Stem Cell Stories That Caught Our Eye: Three new ways to target cancer stem cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:

Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.

Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.

In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:

“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”

 

A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.

They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.

In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:

“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”

 

Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.

The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.

At left, head and neck squamous cell carcinoma invasive growth, and at right, cancer stem cells (shown in red) in head and neck squamous cell carcinoma. (Image Demeng Chen and Cun-Yu Wang/UCLA)

After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.

In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:

“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”

A Clinical Trial Network Focused on Stem Cell Treatments is Expanding

Geoff Lomax is a Senior Officer of CIRM’s Strategic Initiatives.

California is one of the world-leaders in advancing stem cell research towards treatments and cures for patients with unmet medical needs. California has scientists at top universities and companies conducting cutting edge research in regenerative medicine. It also has CIRM, California’s Stem Cell Agency, which funds promising stem cell research and is advancing stem cell therapies into clinical trials. But the real clincher is that California has something that no one else has: a network of medical centers dedicated to stem cell-based clinical trials for patients. This first-of-its-kind system is called the CIRM Alpha Stem Cell Clinics Network.

Get to Know Our Alpha Clinics

In 2014, CIRM launched its Alpha Stem Cell Clinics Network to accelerate the development and delivery of stem cell treatments to patients. The network consists of three Alpha Clinic sites at UC San Diego, City of Hope in Duarte, and a joint clinic between UC Los Angeles and UC Irvine. Less than three years since its inception, the Alpha Clinics are conducting 34 stem cell clinical trials for a diverse range of diseases such as cancer, heart disease and sickle cell anemia. You can find a complete list of these clinical trials on our Alpha Clinics website. Below is an informational video about our Alpha Clinics Network.

So far, hundreds of patients have been treated at our Alpha Clinics. These top-notch medical centers use CIRM-funding to build teams specialized in overseeing stem cell trials. These teams include patient navigators who provided in-depth information about clinical trials to prospective patients and support them during their treatment. They also include pharmacists who work with patients’ cells or manufactured stem cell-products before the therapies are given to patients. And lastly, let’s not forget the doctors and nurses that are specially trained in the delivery of stem cell therapies to patients.

The Alpha Clinics Network also offers resources and tools for clinical trial sponsors, the people responsible for conducting the trials. These include patient education and recruitment tools and access to over 20 million patients in California to support successful recruitment. And because the different clinical trial sites are in the same network, sponsors can benefit from sharing the same approval measures for a single trial at multiple sites.

Looking at the big picture, our Alpha Clinics Network provides a platform where patients can access the latest stem cell treatments, and sponsors can access expert teams at multiple medical centers to increase the likelihood that their trial succeeds.

The Alpha Clinics Network is expanding

This collective expertise has resulted in a 3-fold (from 12 to 36 – two trials are being conducted at two sites) increase in the number of stem cell clinical trials at the Alpha Clinic sites since the Network’s inception. And the number continues to rise every quarter. Given this impressive track record, CIRM’s Board voted in February to expand our Alpha Clinics Network. The Board approved up to $16 million to be awarded to two additional medical centers ($8 million each) to create new Alpha Clinic sites and work with the current Network to accelerate patient access to stem cell treatments.

CIRM’s Chairman Jonathan Thomas explained,

Jonathan Thomas

“We laid down the foundation for conducting high quality stem cell trials when we started this network in 2014. The success of these clinics in less than three years has prompted the CIRM Board to expand the Network to include two new trial sites. With this expansion, CIRM is building on the current network’s momentum to establish new and better ways of treating patients with stem cell-based therapies.”

The Alpha Clinics Network plays a vital role in CIRM’s five-year strategic plan to fund 50 new clinical trials by 2020. In fact, the Alpha Clinic Network supports clinical trials funded by CIRM, industry sponsors and other sources. Thus, the Network is on track to becoming a sustainable resource to deliver stem cell treatments indefinitely.

In addition to expanding CIRM’s Network, the new sites will develop specialized programs to train doctors in the design and conduct of stem cell clinical trials. This training will help drive the development of new stem cell therapies at California medical centers.

Apply to be one our new Alpha Clinics!

For the medical centers interested in joining the CIRM Alpha Stem Cell Clinics Network, the deadline for applications is May 15th, 2017. Details on this funding opportunity can be found on our funding page.

The CIRM Team looks forward to working with prospective applicants to address any questions. The Alpha Stem Cell Clinics Network will also be showcasing it achievement at its Second Annual Symposium, details may be found on the City of Hope Alpha Clinics website.

City of Hope Medical Center and Alpha Stem Cell Clinic


Related Links:

3D printing blood vessels: a key step to solving the organ donor crisis

About 120,000 people in the U.S. are on a waiting list for an organ donation and every day 22 of those people will die because there aren’t enough available organs. To overcome this organ donor crisis, bioengineers are working hard to develop 3D printing technologies that can construct tissues and organs from scratch by using cells as “bio-ink”.

Though each organ type presents its own unique set of 3D bioprinting challenges, one key hurdle they all share is ensuring that the transplanted organ is properly linked to a patient’s  circulatory system, also called the vasculature. Like the intricate system of pipes required to distribute a city’s water supply to individual homes, the blood vessels of our circulatory system must branch out and reach our organs to provide oxygen and nutrients via the blood. An organ won’t last long after transplantation if it doesn’t establish this connection with the vasculature.

3d-printing-blood-vessels-2

Digital model of blood vessel network. Photo: Erik Jepsen/UC San Diego Publications

In a recent UC San Diego (UCSD) study, funded in part by CIRM, a team of engineers report on an important first step toward overcoming this challenge: they devised a new 3D bioprinting method to recreate the complex architecture of blood vessels found near organs. This type of 3D bioprinting approach has been attempted by other labs but these earlier methods only produced simple blood vessel shapes that were costly and took hours to fabricate.  The UCSD team’s home grown 3D bioprinting process, in comparison, uses inexpensive components and only takes seconds to complete. Wei Zhu, the lead author on the Biomaterials publication, expanded on this comparison in a press release:

wzhu

Wei Zhu

“We can directly print detailed microvasculature structures in extremely high resolution. Other 3D printing technologies produce the equivalent of ‘pixelated’ structures in comparison and usually require … additional steps to create the vessels.”

 

As a proof of principle, the bioprinted vessel structures – made with two human cell types found in blood vessels – were transplanted under the skin of mice. After two weeks, analysis of the skin showed that the human grafts were thriving and had integrated with the mice’s blood vessels. In fact, the presence of red blood cells throughout these fused vessels provided strong evidence that blood was able to circulate through them. Despite these promising results a lot of work remains.

3d-printing-blood-vessels-3

Microscopic 3D printed blood vessel structure. Photo: Erik Jepsen/UC San Diego Publications

As this technique comes closer to a reality, the team envisions using induced pluripotent stem cells to grow patient-specific organs and vasculature which would be less likely to be rejected by the immune system.

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Shaochen Chen

“Almost all tissues and organs need blood vessels to survive and work properly. This is a big bottleneck in making organ transplants, which are in high demand but in short supply,” says team lead Shaochen Chen. “3D bioprinting organs can help bridge this gap, and our lab has taken a big step toward that goal.”

 

We eagerly await the day when those transplant waitlists become a thing of the past.

License to heal: UC Davis deal looks to advance stem cell treatment for bone loss and arthritis

Nancy Lane

Wei Yao and Nancy Lane of UC Davis: Photo courtesy UC Davis

There are many challenges in taking even the most promising stem cell treatment and turning it into a commercial product approved by the Food and Drug Administration (FDA). One of the biggest is expertise. The scientists who develop the therapy may be brilliant in the lab but have little experience or expertise in successfully getting their work through a clinical trial and ultimately to market.

That’s why a team at U.C. Davis has just signed a deal with a startup company to help them move a promising stem cell treatment for arthritis, osteoporosis and fractures out of the lab and into people.

The licensing agreement combines the business acumen of Regenerative Arthritis and Bone Medicine (RABOME) with the scientific chops of the UC Davis team, led by Nancy Lane and Wei Yao.

They plan to test a hybrid molecule called RAB-001 which has shown promise in helping direct mesenchymal stem cells (MSCs) – these are cells typically found in the bone marrow and fat tissue – to help stimulate bone growth and increase existing bone mass and strength. This can help heal people suffering from conditions like osteoporosis or hard to heal fractures. RAB-001 has also shown promise in reducing inflammation and so could prove helpful in treating people with inflammatory arthritis.

Overcoming problems

In a news article on the UC Davis website, Wei Yao, said RAB-001 seems to solve a problem that has long puzzled researchers:

“There are many stem cells, even in elderly people, but they do not readily migrate to bone.  Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”

The UC Davis team already has approval to begin a Phase 1 clinical trial to test this approach on people with osteonecrosis, a disease caused by reduced blood flow to bones. CIRM is funding this work.

The RABOME team also hopes to test RAB-001 in clinical trials for healing broken bones, osteoporosis and inflammatory arthritis.

CIRM solution

To help other researchers overcome these same regulatory hurdles in developing stem cell therapies CIRM created the Stem Cell Center with QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider that has deep experience and therapeutic expertise. The Stem Cell Center will help researchers overcome the challenges of manufacturing and testing treatments to meet FDA standards, and then running a clinical trial to test that therapy in people.

Could Stem Cells Help Beat Multiple Sclerosis?

March is Multiple Sclerosis month. In honor of MS patients and research, we are featuring a guest blog from scientist and communicator Hamideh Emrani. Thoughts expressed here are not necessarily those of CIRM.

If you are reading this post, other than out of curiosity, chances are that you know someone who has been affected by Multiple Sclerosis (MS). This unpredictable and at times confusing disease has affected too many people in my circle of friends and family. I personally have spent hours reading about it and reading about possible treatments.

For instance, M, a really close friend of mine woke up one day and everything was blurry. She could see but it seemed as if there was a thick fog covering everything. After seeing her optometrist and being evaluated via multiple tests and an MRI scan, she was diagnosed with MS. The reason behind her blurred vision was inflammation of her optic nerves.

Why do MS symptoms happen?

The nerve cells in the brain and spinal cord are connected through cellular extensions. Each cell has one long cellular extension at one end, called an axon, that looks similar to an electrical wire. Axons relay information using neural signals from one cell to another. Just as an electrical wire has a protective plastic cover to avoid leakage of electricity, these axons, are covered with a protective layer of a special fat called myelin.

The myelin on the outside of nerve cells is destroyed in patients with MS. (Source Wikimedia & Bruce Blaus)

In MS, a patient’s immune cells start to attack this protective layer in the central nervous system: the optic nerves, brain, and the spinal cord. They also attack the cells that produce myelin (called oligodendrocytes) and the injured nerve axon fibers. This results in de-myelination or the loss of myelin; and eventual deterioration and damage of the nerve axons. In turn, multiple scar tissues form on the damaged areas on nerves that can be seen through MRI, hence the name “multiple sclerosis” with sclerosis meaning scar tissue.

Generally, the demyelination and scar tissue will cause communication problems among nerves and the symptoms vary in each patient making it a complicated disease to treat. Some common resulting symptoms include excessive fatigue, pain, blurred vision, walking difficulties, muscle  stiffness and changes in brain-based skills such as memory and problem solving.

Depending on the stage of the disease and the extent of the damage, the disease has been categorized to four different courses.

MS Type Description
Clinically Isolated Syndrome (CIS) The person has had one episode of neurological symptoms that may or may not be accompanied by damages seen in an MRI scan.

 

Relapsing remitting MS (RRMS) The most common type of MS, which is characterized by clearly defined periods of neurologic inflammation called “MS attacks” that can be followed by periods of partial or complete recovery. The person might be completely symptom free during these remission times.
Secondary progressive MS (SPMS) Many patients with RRMS over time transition to SPMS where there is no recovery from the symptoms and disability accumulates.

 

Primary progressive MS (PPMS) There are no remissions from the onset of the disease and disability caused by disease activity worsens over time.

What is the cause of MS?

MS is affecting a growing number of human populations. While the jury is still out to define the main cause, many scientists believe that various factors play a role such as genetic predisposition, viral and bacterial infections, and environmental cues. MS is mostly prominent in countries in the Northern hemisphere and colder climates. It affects more women than men, and is mostly diagnosed between the age of 35-50.

Treatments for MS

Unfortunately, there is no cure for MS at the moment. The drugs that are available, called MS modifying treatments, try to prevent the progression of the disease but they don’t reverse it. Instead, the drugs mostly modulate the immune system to avoid further attacks or treat symptoms such as fatigue, pain, and bladder issues that are caused by the damage.

How do stem cells come into picture?

Stem cells are unique cells with the ability to both self-renew and specialize into different cell types. This amazing regeneration ability has turned them into great sources for designing treatment strategies to replace the damaged cells in MS. Two stem cell treatment approaches for MS are currently in development. In one, the researchers try to reboot or modulate the patient’s immune system to prevent it from attacking the nerve cells. In the other, scientists focus on using stem cells to make oligodendrocytes to try and regenerate and repair lost and injured nervous tissue.

Overview of Recent Clinical Trials

The most common stem cells used in clinical trials are the blood, or haematopoietic stem cells (HSCs) which are isolated from the bone marrow. Haematopoietic stem cell transplants (HSCT) have been used for decades to treat blood cancers such as leukemias, but the first time they were studied for treating MS was in the 1990s.

In this method, the patient’s HSCs are collected from the bone marrow and stored. Then, the patient’s immune system, including the bone marrow, is completely depleted through chemotherapy. Finally, the stem cells are transplanted back into the body and after a few months eventually build up a new immune system.

Just last month, Dr. Paolo Muraro et al. published a report that reviews such clinical trials and the long-term outcomes for the patients. They evaluated data for 281 patients from 25 centers in 13 countries that were followed an average of 6.5 years after the transplant. At the end they conclude that almost half of the patients receiving HSCT did not have any progression of the disease. And, younger patients with the most common form of MS, RRMS, who had less disability going into the trial, and had gone through less disease modifying treatments had a better outcome. (73% were progression free at the  5 year mark).

Additionally, over the past two years three separate phase two clinical trials in Northern America have reported results:

  • In the HALT-MS trial, a small number (24) of patients with, RRMS, whose disease was not controlled by any medications, underwent HSCT. After 5 years, 91.3% of the patients did not show any sign of disease progression.
  • In June 2016, a Canadian team of researchers reported the results of a long term follow up of an aHSCT trial (the “a” stands for autologous, meaning it used the patient’s own cells) on 24 patients whose MS had progressed even after receiving conventional treatments. After up to 13 years after the transplantation, no relapses were evident, and 35% of the patients experienced reversals in their level of disability.
  • Back in 2015, Burt et al. reported their HSCT treatment regimen for 123 RRMS patients and their follow up of up to 4 years. In their study, instead of completely depleting the patient’s immune system, they just suppressed it and performed the transplants. Their data suggest that there was no disease progression in 87% of individuals who had MS for less than 10 years.

Will Stem Cells be used for treatment of MS in the near future?

Even though the initial results of the HSCT clinical trials sound promising, the risks that are involved are not easy to ignore.  In all the mentioned trials, there were side effects related to the transplant. There were also a total of nine deaths reported in all the studies combined (since 1990s). However, most of these deaths occurred before the year of 2000 and they were attributed to transplantation techniques and patient selection methods. Over the years, researchers have been working hard to fine tune the techniques and made the procedure safer. But even now it is important for the patients to weigh the benefits and the risks before undergoing the procedure.

That’s why neurologists and stem cell scientists do not currently recommend  blood stem cell transplants as the top-of-the-line treatment option for most MS patients. Other types of stem cells are being investigated for their potential in deriving oligodendrocytes and nerve cells to re-myelinate and repair the damaged ones. However, they are still in development and have not reached a clinical trial in people.

At the moment, many stem cell treatment approaches are all at the experimental level and more research is needed to completely prove them to be safe and effective. There are many trusted sources to get information from and the international society for stem cell research (ISSCR) has produced a great nine step guideline for patients and family members considering stem cell treatments. Also the national MS society website is a great resource for learning more about Multiple Sclerosis, including participating in clinical trial studies.


Hamideh Emrani

Hamideh Emrani is a science and technology communicator in Toronto, Canada. She is a graduate of UC Berkeley and has a Masters degree from the University of Toronto. You can follow Hamideh on Twitter.

Stem cell stories that caught our eye: building an embryo and reviving old blood stem cells

Building an embryo in the lab from stem cells
The human body has been studied for centuries yet little is known about the first 14 days of human development when the fertilized embryo implants into the mother’s uterus and begins to divide and grow. Being able to precisely examine this critical time window may help researchers better understand why 75% of conceptions never implant and why 30% of pregnancies end in miscarriage.

This lack of knowledge is due in part to a lack of embryos to study. Researchers rely on embryos donated by couples who’ve gone through in vitro fertilization to get pregnant and have left over embryos that are otherwise discarded. Using mouse stem cells, a research team from Cambridge University reports today in Nature that they’ve generated a cellular structure that has the hallmarks of a fertilized embryo.

embryo

Stem cell-modeled mouse embryo (left) Mouse embryo (right); The red part is embryonic and the blue extra-embryonic.
Credit: Sarah Harrison and Gaelle Recher, Zernicka-Goetz Lab, University of Cambridge

This technique has been tried before without success. The breakthrough here was in the types of cells used. Rather that only relying on embryonic stems cells (ESCs), this study also included extra-embryonic trophoblast stem cells (TSCs), the cell type that goes on to form the placenta.

When grown on a 3D scaffold made from biological materials, the two cell types self-organized themselves into a pattern that closely resembles the early development of a true embryo. In a press release that was picked up by many media outlets, senior author Zernicka-Goetz spoke about the importance of including both TSCs and ESCs:

“We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other. Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn’t take place properly.”

The researchers think that lab-made embryos from mouse or human stem cells have little chance of developing into a fetus because other cell types critical for continued growth are not included. And there’s much to be learned by focusing on these very early events:

“We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos.  Knowing how development normally occurs will allow us to understand why it so often goes wrong,” says Zernicka-Goetz.

Reviving old blood stem cells, part 1: repair the garbage collectors
One of the reasons that our bodies begin to deteriorate in old age is a weakening, dysfunctional immune system that increases the risk for serious infection, blood cancers and chronic inflammatory diseases like atherosclerosis (hardening of the arteries). Reporting this week in Nature, a UCSF research team presents evidence that a breakdown in our cell’s natural garbage collecting system may be partially to blame.

The team focused on a process called autophagy (literally meaning self “auto”-eating “phagy”) that keeps cells functioning properly by degrading faulty proteins and cellular structures. In particular, they examined autophagy in blood-forming stem cells, which give rise to all the cell types of the immune system. They found that autophagy was not working in 70 percent of blood stem cells from old mice. And these cells had all the hallmarks of an old cell. And the other 30 percent? In those cells, autophagy was fully functional and they looked like blood stem cells found in young mice.

The team went on to show that in blood stem cells, autophagy had an additional role that until now had not been observed: it helped slow the activity of the stem cells back to its default state by gobbling up excess mitochondria, the structures that produces a cell’s energy needs. Without this quieting of the stem cell, the over-active mitochondria led to chemical modification of the cell’s DNA that disrupted the blood stem cells’ ability to give rise to a proper balance of immune cells. In fact, young mice with genetic modifications that block autophagy generated blood stem cells with these old age-related characteristics.

But the researchers were also able to restore autophagy in blood stem cells collected from old mice by adding various drugs. Team lead Emmanuelle Passegué is optimistic this result could be translated into a therapeutic approach:

“This discovery might provide an interesting therapeutic angle to use in re-activating autophagy in all of the old HSCs, to slow the aging of the blood system and to improve engraftment during bone marrow or HSC transplantation,” Passegué said in a university press release.

Reviving old blood stem cells, part 2: fix the aging neighborhood
Another study this week focused on age-related disruptions in the function of blood stem cells but in this case an aging neighborhood is to blame. Blood stem cells form and hang out in areas of the bone marrow called niches. Researchers at the Cincinnati Children’s Hospital Medical Center and the University of Ulm in Germany reported this week in EMBO that the age of the niche affects blood stem cell function.

bonemarrow

Microscopy of bone marrow. Red staining indicates osteopotin, blue staining indicates cell nuclei. Credit: University of Ulm

 

When blood stem cells from two-year old mice were transplanted into the bone marrow of eight-week old mice, the older stem cells took on characteristics of young stem cells including an enhance ability to form all the different cell types of the immune system. In trying to understand what was going on, the researchers focused on a bone marrow cell called an osteoblast which gives rise to bone. Osteoblasts produce osteopontin, a protein that plays an important role in the structure of the bone marrow. The team showed that as the bone marrow ages, osteopontin levels go down. And this reduction had effects on the health of blood stem cells. But, as team lead Hartmut Geiger mentions in a press release, this impact could be reversed which points to a potential new therapeutic strategy for age-related disease:

“We show that the place where HSCs form in the bone marrow loses osteopontin upon aging, but if you give back the missing protein to the blood-forming cells they suddenly rejuvenate and act younger. Our study points to exciting novel ways to have a better immune system and possibly less blood cancer upon aging by therapeutically targeting the place where blood stem cells form.”