Imagine growing up without an ear, or with one that was stunted and deformed. It would likely have an impact on almost every part of your life, not just your hearing. But now scientists in China say they have found a way to help give children born with this condition a new ear, one that is grown using their own cells.
Microtia is a rare condition where children are born with a deformed or underdeveloped outer ear. This is what it can look like.
In an interview in New Scientist, Dr. Tessa Hadlock, at Massachusetts Eye and Ear Infirmary in Boston, said:
“Children with the condition often feel self-conscious and are picked on, and are unable to wear glasses.”
In the past repairing it required several cosmetic surgeries that had to be repeated as the child grew. But now Chinese scientists say they have helped five children born with microtia grown their own ears.
In the study, published in the journal EBioMedicine, the researchers explained how they used a CT scan of the child’s normal ear to create a 3D mold, using biodegradable material. They took cartilage cells from the child’s ear, grew them in the lab, and then used them to fill in tiny holes in the ear mold. Over the course of 12 weeks the cells continued to multiply and grow and slowly replaced the biodegradable material in the mold.
While the new “ear” was being prepared in the lab, the scientists used a mechanical device to slowly expand the skin on the child’s affected ear. After 12 weeks there was enough expanded skin for the scientists to take the engineered ear, surgically implant it on the child’s head, and cover it with skin.
Over the course of the next two and a half years the engineered ear took on a more and more “natural” appearance. The children did undergo minor surgeries, to remove scar tissue, but other than that the engineered ear shows no signs of complications or of being rejected.
Here is a photo montage showing the pre and post-surgical pictures of a six-year old girl, the first person treated in the study.
Other scientists, in the US and UK, are already working on using stem cells taken from the patient’s fat tissue, that are then re-engineered to become ear cells.
Surgeons, like Dr. Hadlock, say this study proves the concept is sound and can make a dramatic difference in the lives of children.
“It’s a very exciting approach. They’ve shown that it is possible to get close to restoring the ear structure.”
Nothing makes a professional sports team prouder than its homegrown talent. Training and mentoring a promising, hard-working athlete who eventually helps carry the team to a championship can lift the spirits of an entire city.
Brian Fury
Here at CIRM, we hold a similar sense of pride in Brian Fury, one of our own homegrown all-stars. Nearly a decade ago, Brian was accepted into the inaugural class of CIRM’s Bridges program which provides paid stem cell research internships to students at California universities and colleges that don’t have major stem cell research programs. The aim of the program, which has trained over 1200 students to date, is to build the stem cell work force here in California to accelerate stem cell treatments to patients with unmet medical needs.
A CIRM full circle Today, Brian is doing just that as manager of manufacturing at the UC Davis Institute for Regenerative Cures (IRC) where he leads the preparation of stem cell therapy products for clinical trials in patients. It was at UC Davis that he did his CIRM Bridges internship as a Sacramento State masters student back in 2009. So, he’s really come full circle, especially considering he currently works in a CIRM-funded facility and manufactures stem cell therapy products for CIRM-funded clinical trials.
Gerhard Bauer
“Many of the technicians we have in the [cell manufacturing] facility are actually from the Bridges program CIRM has funded, and were educated by us,” Gerhard Bauer, Brian’s boss and director of the facility, explained to me. “Brian, in particular, has made me incredibly proud. To witness that the skills and knowledge I imparted onto my student would make him such an integral part of our program and would lead to so many novel products to be administered to people, helping with so many devastating diseases is a very special experience. I treasure it every day.”
“It sustains me” Brian’s career path wasn’t always headed toward stem cell science. In a previous life, he was an undergrad in computer management information systems. It was a required biology class at the time that first sparked his interest in the subject. He was fascinated by the course and was inspired by his professor, Cathy Bradshaw. He still recalls a conversation he had with her to better understand her enthusiasm for biology:
“I asked her, ‘what is it about biology that really made you decide this is what you wanted to do?’ And she just said, ‘It sustains me. It is air in my lungs.’ It was what she lived and breathed. That really stuck with me early on.“
Still, Brian went on to earn his computer degree and worked as a computer professional for several years after college. But when the dot com boom went bust in the early 2000’s, Brian saw it as a sign to re-invent himself. Remembering that course with Professor Bradshaw, he went back to school to pursue a biology degree at Sacramento State University.
On a path before there was a path Not content with just his textbooks and lectures at Sac State, Brian offered to volunteer in any lab he could find, looking for opportunities to get hands-on experience:
Brian at work during his Sacramento State days.
“I was really hungry to get involved and I really wanted to not just be in class and learning about all these amazing things in biology but I also wanted to start putting them to work. And so, I looked for any opportunity that I could to become actively involved in actually seeing how biology really works and not just the theory.”
This drive to learn led to several volunteer stints in labs on campus as well as a lab manager job. But it was an opportunity he pursued as he was finishing up his degree that really set in motion his current career path. Gerhard Bauer happened to be giving a guest lecture at Sac State about UC Davis’ efforts to develop a stem cell-based treatment for HIV. Hearing that talk was an epiphany for Brian. “That’s really what hooked me in and helped determine that this is definitely the field that I want to enter into. It was my stepping off point.”
Brian Fury (center) flanked by mentors Gerhard Bauer (left) and Jan Nolta (right)
Inspired, Brian secured a volunteering gig on that project at UC Davis – along with all his other commitments at Sac State – working under Bauer and Dr. Jan Nolta, the director of the UC Davis Stem Cell Program.
That was 2008 and this little path Brian was creating by himself was just about to get some serious pavement. The next year, Sacramento State was one of sixteen California schools that was awarded the CIRM Bridges to Stem Cell Research grant. Their five-year, $3 million award (the total CIRM investment for all the schools was over $55 million) helped support a full-blown, stem cell research-focused master’s program which included 12-month, CIRM-funded internships. One of the host researchers for the internships was, you guessed it, Jan Nolta at UC Davis.
Good Manufacturing Practice (GMP) was a good move Applying to this new program was a no brainer for Brian and, sure enough, he was one of ten students selected for the first-year class. His volunteer HIV project in the Nolta lab seamlessly dovetailed into his Bridges internship project. He was placed under the mentorship of Dr. Joseph Anderson, a researcher in the Nolta lab at the time, and gained many important skills in stem cell research. Brian’s project focused on a stem cell and gene therapy approach to making HIV-resistant immune cells with the long-term goal of eradicating the virus in patients. In fact, follow on studies by the Anderson lab have helped lead to a CIRM-funded clinical trial, now underway at UC Davis, that’s testing a stem cell-based treatment for HIV/AIDs patients.
After his Bridges internship came to a close, Brian worked on a few short-term research projects at UC Davis but then found himself in a similar spot: needing to strike out on a career path that wasn’t necessarily clearly paved. He reached out to Nolta and Bauer and basically cut to the chase in an email asking, “do you know anybody?”. Bauer reply immediately, “yeah, me!”. It was late 2011 and UC Davis had built a Good Manufacturing Practice (GMP) facility with the help of a CIRM Major Facility grant. Bauer only had one technician at the time and work was starting to pick up.
The Good Manufacturing Practice (GMP) facility in UC Davis’ Institute for Regenerative Cures.
A GMP facility is a specialized laboratory where clinical-grade cell products are prepared for use in people. To ensure the cells are not contaminated, the entire lab is sealed off from the outside environment and researchers must don full-body lab suits. We produced the video below about the GMP facility just before it opened.
Bauer knew Brian would be perfect at their GMP facility:
“Brian was a student in the first cohort of CIRM Bridges trainees and took my class Bio225 – stem cell biology and manufacturing practices. He excelled in this class, and I also could observe his lab skills in the GMP training part incorporated in this class. I was very lucky to be able to hire Brian then, since I knew what excellent abilities he had in GMP manufacturing.”
CIRM-supported student now supporting CIRM-funded clinical trials
Brian Fury suited up in GMP facility
Since then, Brian has worked his way up to managing the entire GMP facility and its production of cell therapy products. At last count, he and the five people he supervises are juggling sixteen cell manufacturing projects. One of his current clients is Angiocrine which has a CIRM-funded clinical trial testing a cell therapy aimed to improve the availability and engraftment of blood stem cell transplants. This treatment is geared for cancer patients who have had their cancerous bone marrow removed by chemotherapy.
When a company like Angiocrine approaches Brian at the GMP facility, they already have a well-defined method for generating their cell product. Brian’s challenge is figuring out how to scale up that process to make enough cells for all the patients participating in the clinical trial. And on top of that, he must design the procedures for the clean room environment of the GMP facility, where every element of making the cells must be written down and tracked to demonstrate safety to the Food and Drug Administration (FDA).
The right time, the right place…and a whole bunch of determination and passion It’s extremely precise and challenging work but that’s what makes it so exciting for Brian. He tells me he’s never bored and always wakes up looking forward to what each day’s challenges will bring and figuring out how he and his team are going get these products into the clinic. It’s a responsibility he takes very seriously because he realizes what it means for his clients:
“I invest as much energy and passion and commitment into these projects as I would my own family. This is extremely important to me and I feel so incredibly fortunate to have the opportunity to work on things like this. The reality is, in the GMP, people are bringing their life’s work to us in the hopes we can help people on the other end. They share all their years of development, knowledge and experience and put it in our hands and hope we can scale this up to make it meaningful for patients in need of these treatments.”
Despite all his impressive accomplishments, Brian is a very modest guy using phrases like “I was just in the right place at the right time,” during our conversation. But I was glad to hear him add “and I was the right candidate”. Because it’s clear to me that his determination and passion are the reasons for his success and is the epitome of the type of researcher CIRM had hoped its investment in the Bridges program and our SPARK high school internship program would produce for the stem cell research field.
That’s why we’ll be brimming over with an extra dose of pride on the day that one of Brian’s CIRM-funded stem cell therapy products reaches the goal line with an FDA approval.
Last week, at the World Stem Cell Summit in Miami, CIRM took part in a panel discussion about the role and importance of Alpha Clinics in not just delivering stem cell therapies, but in helping create a new, more collaborative approach to medicine. The Alpha Clinic concept is to create a network of top medical centers that specialize in delivering stem cell clinical trials to patients.
The panel was moderated by Dr. Tony Atala, Director of the Wake Forest Institute for Regenerative Medicine. He said the term Alpha Clinic came from CIRM and the Alpha Stem Cell Clinic Network that we helped create. That network now has five specialist health care centers that deliver stem cell therapies to patients: UC San Diego, UCLA/UC Irvine, City of Hope, UC Davis, and UCSF/Children’s Hospital Oakland.
This is a snapshot of that conversation.
Alpha Clinics Advancing Stem Cell Trials
Dr. Maria Millan, CIRM’s President & CEO:
“The idea behind the Alpha Stem Cell Clinic Network is that CIRM is in the business of accelerating treatments to patients with unmet medical needs. We fund research from the earliest discovery stage to clinical trials. What was anticipated is that, if the goal is to get these discoveries into the clinics then we’ll need a specific set of expertise and talents to deliver those treatments safely and effectively, to gather data from those trials and move the field forward. So, we set out to create a learning network, a sharing network and a network that is more than the sum of its parts.”
“What we learned is that having the Alpha Stem Cell Clinic concept helps investigators in other areas learn from what earlier researchers have done, helping accelerate their work.
For example, we have had a lot of experience in working with rare diseases and we can use the experience we have in treating one disease area in working in others. This shared experience can help us develop deeper understanding in terms of delivering therapies and dosing.”
Susan Solomon, CEO New York Stem Cell Foundation Research Institute. NYSCF has several clinical trials underway. She says in the beginning it was hard finding reputable clinics that could deliver these potentially ground breaking but still experimental therapies:
“My motivation was born out of my own frustration at the poor choices we had in dealing with some devastating diseases, so in order to move things ahead we had to have an alpha clinic that is not just doing clinical trials but is working to overcome obstacles in the field.”
Greg Simon represented the, Biden Cancer Initiative, whose mission is to develop and drive implementation of solutions to accelerate progress in cancer prevention, detection, diagnosis, research, and care, and to reduce disparities in cancer outcomes. He says part of the problem is that people think there are systems already in place that promote collaboration and cooperation, but that’s not really the case.
“In the Cancer Moonshot and the Biden Cancer Initiative we are trying to create the cancer research initiative that people think we already have. People think doctors share knowledge. They don’t. People think they can just sign up for clinical trials. They can’t. People think there are standards for describing a cancer. There aren’t. So, all the things you think you know about the science behind cancer are wrong. We don’t have the system people think is in place. But we want to create that.
If we are going to have a unified system we need common standards through cancer research, shared knowledge, and clinical trial reforms. All my professional career it was considered unethical to refer to a clinical trial as a treatment, it was research. That’s no longer the case. Many people are now told this is your last best hope for treatment and it’s changed the way people think about clinical trials.”
The Process
Maria Millan says we are seeing these kinds of change – more collaboration, more transparency – taking place across the board:
“We see the research in academic institutions that then moved into small companies that are now being approved by the FDA. Academic centers, in conjunction with industry partners, are helping create networks and connections that advance therapies.
This gives us the opportunity to have clinical programs and dialogues about how we can get better, how we can create a more uniform, standard approach that helps us learn from each trial and develop common standards that investigators know have to be in place.
Within the CIRM Alpha Stem Cell Clinic Network the teams coming in can access what we have pulled together already – a database of 20 million patients, a single IRB approval, so that if a cliinical trial is approved for one Alpha Clinic it can also be offered at another.”
Greg Simon says to see the changes really take hold we need to ensure this idea of collaboration starts at the very beginning of the chain:
“If we don’t have a system of basic research where people share data, where people are rewarded for sharing data, journals that don’t lock up the data behind a paywall. If we don’t have that system, we don’t have the ability to move therapies along as quickly as we could.
“Nobody wants to be the last person to die from a cancer that someone figured out a treatment for a year earlier. It’s not that the science is so hard, or the diseases are so hard, it the way we approach them that’s so hard. How do we create the right system?”
More may not necessarily be better
Susan Solomon:
“There are tremendous number of advances moving to the clinic, but I am concerned about the need for more sharing and the sheer number of clinical trials. We have to be smart about how we do our work. There is some low hanging fruit for some clinical trials in the cancer area, but you have to be really careful.”
Greg Simon
“We have too many bad trials, we don’t need more, we need better quality trials.
We have made a lot of progress in cancer. I’m a CLL survivor and had zero problems with the treatment and everything went well.
We have pediatric cancer therapies that turned survival from 10 % to 80%. But the question is why doesn’t more progress happen. We tend to get stuck in a way of thinking and don’t question why it has to be that way. We think of funding because that’s the way funding cycles work, the NIH issues grants every year, so we think about research on a yearly basis. We need to change the cycle.”
Maria Millan says CIRM takes a two pronged approach to improving things, renovating and creating:
“We renovate when we know there are things already in place that can be improved and made better; and we create if there’s nothing there and it needs to be created. We want to be as efficient as we can and not waste time and resources.”
She ended by saying one of the most exciting things today is that the discussion now has moved to how we are going to cover this for patients. Greg Simon couldn’t agree more.
“The biggest predictor of survivability of cancer is health insurance. We need to do more than just develop treatments. We need to have a system that enables people to get access to these therapies.”
(Credit: Jon Enriquez/Mann Lab/Columbia’s Zuckerman Institute).
This rainbow sherbet-colored scientific art is a microscopy image of a fruit fly nervous system in which brain cells were randomly labeled with different colors. It was a figure in a Neuron study published this week showing how cells derived from the same stem cells can go down very different developmental paths but then later are “reunited” to carry out key functions, such as in this case, the nervous system control of leg movements.
Many animal models of Parkinson’s disease are created by mutating specific genes to cause symptoms that mimic this incurable, neurodegenerative disorder. But, by far, most cases of Parkinson’s are idiopathic, a fancy term for spontaneous with no known genetic cause. So, researchers at the Buck Institute took another approach: they generated a mouse model of Parkinson’s disease using the pesticide, paraquat, exposure to which is known to increase the risk of the idiopathic form of Parkinson’s.
Their CIRM-funded study in Cell Reports showed that exposure to paraquat leads to cell senescence – in which cells shut down and stop dividing – particularly in astrocytes, brain cells that support the function of nerve cells. Ridding the mice of these astrocytes relieved some of the Parkinson’s like symptoms. What makes these results so intriguing is the team’s analysis of post-mortem brains from Parkinson’s patients also showed the hallmarks of increased senescence in astrocytes. Perhaps, therapeutic approaches that can remove senescent cells may yield novel Parkinson’s treatments.
Another CIRM-funded study published this week in Nature Neuroscience may also help pave the way to new treatment strategies for neurologic disorders like Parkinson’s disease. A team at Sanford Burnham Prebys Medical Discovery Institute (SBP) discovered a novel gene regulation system that brain stem cells use to maintain their ability to self-renew.
The study centers around messenger RNA, a molecular courier that transcribes a gene’s DNA code and carries it off to be translated into a protein. The team found that the removal of a chemical tag on mRNA inside mouse brain stem cells caused them to lose their stem cell properties. Instead, too many cells specialized into mature brain cells leading to abnormal brain development in animal studies. Team lead Jing Crystal Zhao, explained how this finding is important for future therapeutic development:
Crystal Zhao
“As NSCs are increasingly explored as a cell replacement therapy for neurological disorders, understanding the basic biology of NSCs–including how they self-renew–is essential to harnessing control of their in vivo functions in the brain.”
Our regular readers are most likely familiar with both CRISPR gene editing and induced pluripotent stem cell (iPSC) technologies. But, in case you missed it late last week, a Cell Stem Cell study out of Sheng Ding’s lab at the Gladstone Institutes, for the first time, combined the two by using CRISPR to make iPSCs. The study got a lot of attention including a review by Paul Knoepfler in his blog The Niche. Check it out for more details!
Can you guess what the tiny white balls are in this photo? I’ll give you a hint, they represent the organ that you’re using right now to answer my question.
These are 3D brain organoids generated from human pluripotent stem cells growing in a culture dish. You can think of them as miniature models of the human brain, containing many of the brain’s various cell types, structures, and regions.
Scientists are using brain organoids to study the development of the human nervous system and also to model neurological diseases and psychiatric disorders. These structures allow scientists to dissect the inner workings of the brain – something they can’t do with living patients.
Brain-in-a-Dish
Dr. Sergiu Pasca is a professor at Stanford University who is using 3D cultures to understand human brain development. Pasca and his lab have previously published methods to make different types of brain organoids from induced pluripotent stem cells (iPSCs) that recapitulate human brain developmental events in a dish.
Sergiu Pasca, Stanford University (Image credit: Steve Fisch)
“Using brain tissue grown from patient-derived iPSCs, Dr. Sergiu Pasca and his team recreated the types of nerve cell circuits that form during the late stages of pregnancy in the fetal cerebral cortex, the outer layer of the brain that is responsible for functions including memory, language and emotion. With this system, they observed irregularities in the assembly of brain circuitry that provide new insights into the cellular and molecular causes of neuropsychiatric disorders like autism.”
Pasca generated brain organoids from the iPSCs of patients with a genetic disease called Timothy Syndrome – a condition that causes heart problems and some symptoms of autism spectrum disorder in children. By comparing the nerve cell circuits in patient versus healthy brain organoids, he observed a disruption in the migration of nerve cells in the organoids derived from Timothy Syndrome iPSCs.
“We’ve never been able to recapitulate these human-brain developmental events in a dish before,” said Pasca in a press release, “the process happens in the second half of pregnancy, so viewing it live is challenging. Our method lets us see the entire movie, not just snapshots.”
The Rise of 3D Brain Cultures
Pasca’s lab is just one of many that are working with 3D brain culture technologies to study human development and disease. These technologies are rising in popularity amongst scientists because they make it possible to study human brain tissue in normal and abnormal conditions. Brain organoids have also appeared in the mainstream news as novel tools to study how epidemics like the Zika virus outbreak affect the developing fetal brain (more here and here).
While these advances are exciting and promising, the field is still in its early stages and the 3D organoid models are far from perfect at representing the complex biology of the human brain.
Pasca addresses the progress and the hurdles of 3D brain cultures in a review article titled “The rise of three-dimensional brain cultures” published this week in the journal Nature. The article, describes in detail how pluripotent stem cells can assemble into structures that represent different regions of the human brain allowing scientists to observe how cells interact within neural circuits and how these circuits are disrupted by disease.
The review goes on to compare different approaches for creating 3D brain cultures (see figure below) and their different applications. For instance, scientists are culturing organoids on microchips (brains-on-a-chip) to model the blood-brain barrier – the membrane structure that protects the brain from circulating pathogens in the blood but also makes drug delivery to brain very challenging. Brain organoids are also being used to screen for new drugs and to model complex diseases like Alzheimer’s.
Human pluripotent stem cells, adult stem cells or cancer cells can be used to derive microfluidics-based organs-on-a-chip (top), undirected organoids (middle), and region-specific brain organoids or organ spheroids (bottom). These 3D cultures can be manipulated with CRISPR-Cas9 genome-editing technologies, transplanted into animals or used for drug screening. (Pasca, Nature)
Pasca ends the review by identifying the major hurdles facing 3D brain culture technologies. He argues that “3D cultures only approximate the appearance and architecture of neural tissue” and that the cells and structures within these organoids are not always predictable. These issues can be address over time by enforcing quality control in how these 3D cultures are made and by using new biomaterials that enable the expansion and maturation of these cultures.
Nonetheless, Pasca believes that 3D brain cultures combined with advancing technologies to study them have “the potential to give rise to novel features for studying human brain development and disease.”
He concludes the review with a cautiously optimistic outlook:
“This is an exciting new field and as with many technologies, it may follow a ‘hype’ cycle in which we overestimate its effects in the short run and underestimate its effects in the long run. A better understanding of the complexity of this platform, and bringing interdisciplinary approaches will accelerate our progress up a ‘slope of enlightenment’ and into the ‘plateau of productivity’.”
3D brain culture from the Pasca Lab, Stanford University
Lucas Lidner was left paralyzed below the chin after a truck accident last May. Photo: Fox6Now, Milwaukee
On a Sunday morning in early 2016, Lucas Lindner was driving to get some donuts for his grandmother. A deer jumped in front of his truck. Lucas swerved to avoid it and crashed, suffering a severe spinal cord injury that left him paralyzed from the neck down.
Lucas took part in a CIRM-funded clinical trial, becoming just the second person to get 10 million stem cells transplanted into his neck. Since then he has regained some use of his arms and hands. While some patients with spinal cord injuries do experience what is called “spontaneous” recovery, Lucas was not the only person in the trial who experienced an improvement. Asterias Biotherapeutics, the company behind the clinical trial, reported that four of the six patients in the trial “have recovered 2 or more motor levels on at least one side through 12 months, which is more than double the rates of recovery seen in both matched historical controls and published data in a similar population.”
Lucas says his improvement has changed his life.
“I was pretty skeptical after the accident, on being able to do anything, on what was going to happen. But regaining hand function alone gave me everything I pretty much needed or wanted back.”
Lucas can now type 40 words a minute, use a soldering iron and touch his pinkie to his thumb, something he couldn’t do after the accident.
In August of last year Lucas did something else he never imagined he would be able to do, he threw out the first pitch at a Milwaukee Brewers baseball game. At the time, he said “I’m blown away by the fact that I can pitch a ball again.”
Lucas Lindner at the Milwaukee Brewers baseball game.
Now Lucas has his sights set on something even more ambitious. He is going back to school to study IT.
“When I was in 3rd grade a teacher asked what I want to be and I said a neuro-computational engineer. Everyone laughed at me because no one knew what that meant. Now, after what happened to me, I want to be part of advancing the science, helping make injuries like mine a thing of the past.”
Even though he was one of the first people to take part in this clinical trial, Lucas doesn’t think of himself as a pioneer.
“The real pioneers are the scientists who came up with this therapy, who do it because they love it.”
“In the last three scans, which I have every six weeks, they’re showing that there is no mestastasis (invasive cancer) anywhere in my body. [The doctors] I guess were quite blown away because they didn’t expect [the treatment] to be so quick or to be that complete.”
Today we’re sharing the story of Tom Howing, who took part in Forty Seven, Inc.’s CIRM-funded clinical trial that’s testing an innovative treatment for cancer.
The two-minute video below sums up Tom’s address to CIRM’s governing Board back in December. During his talk, he gave a personal perspective on his cancer diagnosis, the promising but ultimately disappointing results of standard anti-cancer treatments and the remarkable results he’s experienced from Forty Seven’s clinical trial.
Steven Deitcher, President and CEO of Medeor Therapeutics, receives $18.8 million clinical award from CIRM to fund Phase 3 trial to help kidney transplant patients. (Photo: Todd Dubnicoff/CIRM)
Last week, CIRM’s governing Board approved funding for a Phase 3 clinical trial testing a stem cell-based treatment that could eliminate the need for immunosuppressive drugs in some patients receiving kidney transplants.
Over 650,000 Americans suffer from end-stage kidney disease – a life-threatening condition caused by the loss of kidney function. The best available treatment for these patients is a kidney transplant from a genetically matched, living donor. However, patients who receive a transplant must take life-long immunosuppressive drugs to prevent their immune system from rejecting the transplanted organ. Over time, these drugs are toxic and can also increase a patient’s risk of infection, heart disease, cancer and diabetes. Despite these drugs, many patients still lose transplanted organs due to rejection.
Reducing or eliminating the need for immunosuppressive drugs in kidney transplant patients is an unmet medical need that our Agency is well aware of. That’s why on Friday at our January ICOC meeting, the CIRM Board voted to invest $18.8 million dollars in a Phase III clinical trial sponsored by Medeor Therapeutics that will address this need head on.
Medeor, a biotechnology company located in San Mateo, California, is developing a stem cell-based therapy, called MDR-101, that they hope will eliminate the need for immunosuppressive drugs in genetically matched kidney transplant patients.
The company takes blood-forming stem cells and immune cells from the organ donor and infuses them into the patient receiving the donor’s kidney. Introducing the donor’s immune cells into the patient creates a condition called “mixed chimerism” where immune cells from the patient and the donor are able to co-exist. In this way, the patient’s immune system is able to adapt to and tolerate the donor’s kidney, potentially eliminating the need for the immunosuppressive drugs that are normally necessary to prevent transplant rejection.
CIRM President and CEO, Dr. Maria Millan, commented in a CIRM news release:
Maria Millan
“These immunosuppressive drugs not only can cause harmful side effects, but they are also expensive and some patients lose their transplant either because they can’t afford to pay for the drugs, or because their effectiveness is not adequate. Medeor’s stem cell-based therapy aims to prevent transplant rejection and eliminate the need for immunosuppression in these kidney transplant patients. If they are successful, this approach could be developed for other organs including heart, liver, and lung transplants.”
CIRM funding will enable Medeor to test their stem cell-based treatment in a Phase 3 clinical trial. If the trial meets its objective in allowing patients to eliminate immunosuppressive drug use without rejection, Medeor may apply to the US Food and Drug Administration (FDA) for permission to market their therapy to patients in the United States.
Dr. Steven Deitcher, co-founder, President and CEO of Medeor, touched on the impact that this CIRM award will have on the advancement of their trial:
“We are very grateful for the financial support and validation from CIRM for the MDR-101 program. CIRM funding accelerates our timelines, and these timelines are what stand between needy patients and potential transformative therapies. This CIRM award combined with investor support represent a public-private collaboration that we hope will make a difference in the lives of organ transplant recipients in California, the entire U.S., and beyond.”
At CIRM we have our focus very clearly on the future, on accelerating stem cell therapies to patients with unmet medical needs. But every once in a while, it’s a good idea to look back at what you have already done. Knowing where you came from can help you get to where you are heading.
So, it’s with a sense of accomplishment that we are unveiling our 2017 Annual Report. It’s a look back at another banner year for the stem cell agency, the research we funded, the partnerships we created and, most importantly, the lives we touched.
It features profiles of several people who received stem cell therapies in CIRM-funded clinical trials and the impact those therapies are having on them. But it also looks at some of the other individuals who are such a vital part of the work we do: patient advocates, researchers and a member of our Grants Working Group which reviews applications for funding. Each one, in their own way, contributes to advancing the field.
The report also highlights some of the less obvious ways that our funding is benefitting California. For example, the additional $1.9 billion dollars our funding has helped generate through co-funding and partnerships, or the number of projects we are funding that have been awarded Regenerative Medicine Advanced Therapy Designation from the Food and Drug Administration (FDA), making them eligible for accelerated review if their results continue to be promising.
It’s a look back at a successful year.
But we are not resting on our laurels. We are already hard at work, determined to make 2018 even better.
This week, UCLA scientist Scott Kitchen made the news for his efforts to develop a CIRM-funded stem cell gene therapy that could potentially cure patients infected with HIV. Kitchen’s work was profiled in the Daily Beast, which argued that his “research could significantly up survival rates from the virus.”
Scott Kitchen, UCLA Medicine
Kitchen and a team of scientists at the UCLA David Geffen School of Medicine are genetically modifying blood-forming, hematopoietic stem cells (HSCs) to express chimeric antigen receptors (CARs) that target HIV-infected cells. CARs are protein complexes on the surface of cells that are designed to recognize specific types of cells and are being developed as powerful immunotherapies to fight cancer and HIV infection.
These CAR-expressing HSCs can be transplanted into patients where they develop into immune cells called T cells and natural killer (NK) cells that will destroy cells harboring HIV. This strategy also aims to make patients resistant to HIV because the engineered immune cells will stick around to prevent further HIV infection.
By engineering a patient’s own blood-forming stem cells to produce an unlimited supply of HIV-resistant immune cells that can also eradicate HIV in other cells, Kitchen and his team are creating the possibility for a life-long, functional cure.
Dr. Kelly Shepard, Senior Science Officer of Discovery and Translation Research at CIRM, reflected on significance of Kitchen’s research in an interview:
Kelly Shepard
“This unique approach represents a two-pronged strategy whereby a patient’s own stem cells are engineered not only to be protected from new HIV infection, but also to produce HIV-specific CAR T cells that will seek out and destroy existing and new pools of HIV infection in that patient, ideally leading to a lifelong cure.”
Kitchen and his team are currently testing this stem cell-based CAR-T therapy against HIV in a large-animal model. Their latest findings, which were published recently in the journal PLOS Pathogens, showed that stem cell-derived human CAR T cells were effective at reducing the amount of HIV virus (called the viral load) in their animal-model. They also saw that the CAR T cells survived for more than two years without causing any toxic side effects. This work was funded by an earlier CIRM award led by another CIRM grantee, Dr. Jerome Zack, who is research collaborator of Kitchen’s.
In December 2017, Kitchen received a $1.7 million CIRM Discovery Stage Quest award so that the team can continue to optimize their stem cell CAR T therapy in animal models. Ultimately, they hope to gain insights into how this treatment could be further developed to treat patients with HIV.
Currently, there is no widely available cure for HIV and standard antiretroviral therapies are expensive, difficult for patients to manage and have serious side effects that reduce life expectancy. CIRM has awarded almost $75 million in funding to California scientists focused on developing novel stem cell-based therapies for HIV to address this unmet medical need. Three of these awards support early stage clinical trials, while the rest support earlier stage research projects like Kitchen’s.
CIRM Communications Director, Kevin McCormack, was quoted at the end Daily Beast article explaining CIRM’s strategy for tackling HIV:
“There are a lot of researchers working on developing stem cell therapies for HIV. We fund different approaches because at this stage we don’t know which approach will be most effective, and it may turn out that it’s ultimately a combination of these approaches, or others, that works.”
“The idea behind the Alpha Stem Cell Clinic Network is that CIRM is in the business of accelerating treatments to patients with unmet medical needs. We fund research from the earliest discovery stage to clinical trials. What was anticipated is that, if the goal is to get these discoveries into the clinics then we’ll need a specific set of expertise and talents to deliver those treatments safely and effectively, to gather data from those trials and move the field forward. So, we set out to create a learning network, a sharing network and a network that is more than the sum of its parts.”
“What we learned is that having the Alpha Stem Cell Clinic concept helps investigators in other areas learn from what earlier researchers have done, helping accelerate their work.
“My motivation was born out of my own frustration at the poor choices we had in dealing with some devastating diseases, so in order to move things ahead we had to have an alpha clinic that is not just doing clinical trials but is working to overcome obstacles in the field.”
“In the Cancer Moonshot and the Biden Cancer Initiative we are trying to create the cancer research initiative that people think we already have. People think doctors share knowledge. They don’t. People think they can just sign up for clinical trials. They can’t. People think there are standards for describing a cancer. There aren’t. So, all the things you think you know about the science behind cancer are wrong. We don’t have the system people think is in place. But we want to create that.
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The Stem Cellar 