A colony of iPSCs from a Parkinson’s patient (left) and dopaminergic neurons made from these iPSCs (right) to model PD. (Image credit: Jeanne Loring)
A new study that used adult blood stem cells to create replacement brain nerve cells appears to help rats with Parkinson’s.
In Parkinson’s, the disease attacks brain nerve cells that produce a chemical called dopamine. The lack of dopamine produces a variety of symptoms including physical tremors, depression, anxiety, insomnia and memory problems. There is no cure and while there are some effective treatments they tend to wear off over time.
In this study, researchers at Arizona State University took blood cells from humans and, using the iPSC method, changed those into dopamine-producing neurons. They then cultured those cells in the lab before implanting them in the brains of rats which had Parkinson’s-like symptoms.
They found that rats given cells that had been cultured in the lab for 17 days survived in greater numbers and seemed to be better at growing new connections in their brains, compared to rats given cells that had been cultured for 24 or 37 days.
In addition, those rats given larger doses of the cells experienced a complete reversal of their symptoms, compared to rats given smaller doses.
In a news release, study co-author Dr. Jeffrey Kordower, said: “We cannot be more excited by the opportunity to help individuals who suffer from [a] genetic form of Parkinson’s disease, but the lessons learned from this trial will also directly impact patients who suffer from sporadic, or non-genetic forms of this disease.”
The study, published in the journal npj Regenerative Medicine, says this approach might also help people suffering from other neurological diseases like Alzheimer’s or Huntington’s disease.
Human blood stem cells emerging from specialized endothelial cells in the wall of an embryonic aorta. UCLA scientists’ confirmation of this process clarifies a longstanding controversy about the stem cells’ cellular origin. Image Credit: Hanna Mikkola Lab/UCLA, Katja Schenke-Layland Lab/University of Tübingen, Nature
California researchers from UCLA and colleagues have created a first-of-its-kind roadmap that traces each step in the development of blood stem cells in the human embryo, providing scientists with a blueprint for producing fully functional blood stem cells in the lab.
The research, published in the journal Nature, could help expand treatment options for blood cancers like leukemia and inherited blood disorders such as sickle cell disease, said UCLA’s Dr. Hanna Mikkola, who led the study.
Blood stem cells, also called hematopoietic stem cells, can make unlimited copies of themselves and differentiate into every type of blood cell in the human body. For decades, doctors have used blood stem cells from the bone marrow of donors and the umbilical cords of newborns in life-saving transplant treatments for blood and immune diseases.
However, these treatments are limited by a shortage of matched donors and hampered by the low number of stem cells in cord blood.
Researchers have long sought to create blood stem cells in the lab from human pluripotent stem cells, which can potentially give rise to any cell type in the body. But success has been elusive, in part because scientists have lacked the instructions to make lab-grown cells become self-renewing blood stem cells rather than short-lived blood progenitor cells, which can only produce limited blood cell types.
“Nobody has succeeded in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to generate,” said Mikkola.
A New Roadmap
The new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical for creating cells that are suitable for use in transplantation therapies, said UCLA scientist Vincenzo Calvanese, a co–first author of the research, along with UCLA’s Sandra Capellera-Garcia and Feiyang Ma.
Researchers Vincenzo Calvanese and Hanna Mikkola. | Credit: Eddy Marcos Panos (left); Reed Hutchinson/UCLA
“We now have a manual of how hematopoietic stem cells are made in the embryo and how they acquire the unique properties that make them useful for patients,” said Calvanese, who is also a group leader at University College London.
The research team created the resource using new technologies that enable scientists to identify the unique genetic networks and functions of thousands of individual cells and to reveal the location of these cells in the embryo.
The data make it possible to follow blood stem cells as they emerge and migrate through various locations during their development, starting from the aorta and ultimately arriving in the bone marrow. Importantly, the map unveils specific milestones in their maturation process, including their arrival in the liver, where they acquire the special abilities of blood stem cells.
The research group also pinpointed the exact precursor in the blood vessel wall that gives rise to blood stem cells. This discovery clarifies a longstanding controversy about the stem cells’ cellular origin and the environment that is needed to make a blood stem cell rather than a blood progenitor cell.
Through these insights into the different phases of human blood stem cell development, scientists can see how close they are to making a transplantable blood stem cell in the lab.
A Better Understanding of Blood Cancers
In addition, the map can help scientists understand how blood-forming cells that develop in the embryo contribute to human disease. For example, it provides the foundation for studying why some blood cancers that begin in utero are more aggressive than those that occur after birth.
“Now that we’ve created an online resource that scientists around the world can use to guide their research, the real work is starting,” Mikkola said. “It’s a really exciting time to be in the field because we’re finally going to be seeing the fruits of our labor.”
Immunotherapy is a type of cancer treatment that uses a person’s own immune system to fight cancer. It comes in a variety of forms including targeted antibodies, cancer vaccines, and adoptive cell therapies. While immunotherapies have revolutionized the treatment of aggressive cancers in recent decades, they must be created on a patient-specific basis and as a result can be time consuming to manufacture/process and incredibly costly to patients already bearing the incalculable human cost of suffering from the cruelest disease.
Fortunately, the rapid progress that has led to the present era of cancer immunotherapy is expected to continue as scientists look for ways to improve efficacy and reduce cost. Just this week, a CIRM-funded study published in Cell Reports Medicine revealed a critical step forward in the development of an “off-the-shelf” cancer immunotherapy by researchers at UCLA. “We want cell therapies that can be mass-produced, frozen and shipped to hospitals around the world,” explains Lili Yang, the study’s senior author.
Lili Yang, the study’s senior author and a member of UCLA’s Broad Stem Cell Research Center
In order to fulfil this ambitious goal, Yang and her colleagues developed a new method for producing large numbers of a specialized T cell known as invariant natural killer T (iNKT) cells. iNKT cells are rare but powerful immune cells that don’t carry the risk of graft-versus-host disease, which occurs when transplanted cells attack a recipient’s body, making them better suited to treat a wide range of patients with various cancers.
Using stem cells from donor cord-blood and peripheral blood samples, the team of researchers discovered that one cord blood donation could produce up to 5,000 doses of the therapy and one peripheral blood donation could produce up to 300,000 doses. The high yield of the resulting cells, called hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells,could dramatically reduce the cost of producing immune cell products in the future.
In order to test the efficacy of the HSC–iNKT cells, researchers conducted two very important tests. First, they compared its cancer fighting abilities to another set of immune cells called natural killer cells. The results were promising. The HSC–iNKT cells were significantly better at killing several types of tumor cells such as leukemia, melanoma, and lung cancer. Then, the HSC–iNKT cells were frozen and thawed, just as they would be if they were to one day become an off-the-shelf cell therapy. Researchers were once again delighted when they discovered that the HSC–iNKT cells sustained their tumor-killing efficacy.
Next, Yang and her team added a chimeric antigen receptor (CAR) to the HSC–iNKT cells. CAR is a specialized molecule that can enable immune cells to recognize and kill a specific type of cancer. When tested in the lab, researchers found that CAR-equipped HSC–iNKT cells eliminated the specific cancerous tumors they were programmed to destroy.
This study was made possible in part by three grants from CIRM.
When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.
The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.
The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.
Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.
Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.
CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.
Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.
It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.
Illustration showing the mechanism of an ischemic stroke. In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of that area of the brain. Here, a blood clot is the reason for restricted blood flow.
Stroke is the third leading cause of death and serious long-term disability and affects nearly 800,000 Americans a year, with someone in the U.S. suffering a stroke every 40 seconds. Roughly 87% of all strokes are ischemic strokes, meaning that a clot blocks blood flow to the brain. Unfortunately 90% of those who suffer an ischemic stroke also end up suffering from weakness or paralysis to one side of the body.
A study conducted by Muhammad Haque, Ph.D. and Sean Savitz, M.D. at The University of Texas Health Science Center at Houston (UTHealth) found that treating patients with stem cells from their own bone marrow could lead to a reduction in brain injury after a stroke caused by a blood clot.
For this study, there were 37 patients from ages 18 to 80. While all received the standard stroke treatment and rehabilitation follow-up, 17 patients whose strokes were the most severe received a bone marrow stem cell therapy. To measure any improvement, the UTHealth team used 3D brain imaging of the patients obtained from MRI scans. They used these images to compare changes in white matter of those treated with their own bone marrow stem cells to those who were not treated.
White matter is a specific type of tissue in the brain that is critical for motor function because it is responsible for carrying movement-related information to the spinal cord.
Three months after the stroke, the MRI scans of each patient showed the expected decrease after a stroke. However, scans taken 12 months after the stroke occurred showed an improvement on average in the 17 patients who received bone marrow cell therapy.
In a press release from UTHealth, Dr. Haque elaborates on what these results could mean for developing treamtents for stroke patients.
“We envision that future clinical trials might be directed toward identifying white matter protection or repair as an important mechanistic target of efficacy studies and potency assays for bone marrow cell therapies.”
The full results to this study were published in STEM CELLS Translational Medicine.
Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger
Alpha thalassemia major is, by any stretch of the imagination, a dreadful, heart breaker of a disease. It’s caused by four missing or mutated genes and it almost always leads to a fetus dying before delivery or shortly after birth. Treatments are limited and in the past many parents were told that all they can do is prepare for the worst.
Now, however, there is new hope with new approaches, including one supported by CIRM, helping keep these children alive and giving them a chance at a normal life.
Thalassemias are a group of blood disorders that affect the way the body makes hemoglobin, which helps in carrying oxygen throughout the body. In alpha thalassemia major it’s the lack of alpha globin, a key part of hemoglobin, that causes the problem. Current treatment requires in blood transfusions to the fetus while it is still in the womb, and monthly blood transfusions for life after delivery, or a bone marrow transplant if a suitable donor is identified.
A clinical trial run by University of California San Francisco’s Dr. Tippi MacKenzie – funded by CIRM – is using a slightly different approach. The team takes stem cells from the mother’s bone marrow and then infuses them into the fetus. If accepted by the baby’s bone marrow, these stem cells can then mature into healthy blood cells. The hope is that one day this method will enable children to be born with a healthy blood supply and not need regular transfusions.
Treating these babies, saving their lives, is the focus of a short film from UCSF called “Surviving with Joy”. It’s a testament to the power of medicine, and the courage and resilience of parents who never stopped looking for a way to help their child.
Evie Junior is participating in a CIRM funded clinical trial for sickle cell disease that uses a stem cell gene therapy approach. Image credit: UCLA Broad Stem Cell Research Center
For Evie Junior, personal health and fitness have always been a top priority. During his childhood, he was active and played football, basketball, and baseball in the Bronx, New York. One would never guess that after playing these sports, some nights he experienced pain crises so severe that he was unable to walk. One would also be shocked to hear that he had to have his gallbladder and spleen removed as a child as well.
The health issues that Evie has faced all of his life are related to his diagnosis of sickle cell disease (SCD), a genetic, blood related disorder. SCD causes blood stem cells in the bone marrow, which make blood cells, to produce hard, “sickle” shaped red blood cells. These “sickle” shaped blood cells die early, causing there to be a lack of red blood cells to carry oxygen throughout the body. Due to their “sickle” shape, these cells also get stuck in blood vessels and block blood flow, resulting in excruciating bouts of pain that come on with no warning and can leave patients hospitalized for days.
SCD affects 100,000 people in the United States, the majority of whom are from the Black and Latinx communities, and millions more people around the world,. It can ultimately lead to strokes, organ damage, and early death.
Growing up with SCD inspired Evie to become an emergency medical technician, where he would be able to help patients treat their pain en route to the hospital, in much the same way he has managed his own pain crises for his whole life. Unfortunately as time passed, Evie’s pain crises became harder and harder to manage.
Then in July 2019, Evie decided to enroll in a CIRM funded clinical trial for a stem cell gene therapy to treat SCD. The therapy, developed by Dr. Don Kohn at UCLA, is intended to correct the genetic mutation in a patient’s blood stem cells to allow them to produce healthy red blood cells. Dr. Kohn has already applied the same concept to successfully treat several genetic immune system deficiencies in two other CIRM funded trials, including a cure for a form of Severe Combined Immunodeficiency, also known as bubble baby disease, as well as X-Linked Chronic Granulomatous Disease.
After some delays related to the coronavirus pandemic, Evie finally received an infusion of his own blood stem cells that had been genetically modified to overcome the mutation that causes SCD in July 2020.
Although the results are still very preliminary, so far they look very promising. Three months after his treatment, blood tests indicated that 70% of Evie’s blood stem cells had the new corrected gene. The UCLA team estimates that a 20% correction would be enough to prevent future sickle cell complications. What is also encouraging is that Evie hasn’t had a pain crisis since undergoing the treatment.
In a press release from UCLA, Dr. Kohn discusses that he is cautiously optimistic about these results.
“It’s too early to declare victory, but it’s looking quite promising at this point. Once we’re at six months to a year, if it looks like it does now, I’ll feel very comfortable that he’s likely to have a permanent benefit.”
In the same press release, Evie talks about what a cure would mean for his future and his life going forward.
“I want to be present in my kids’ lives, so I’ve always said I’m not going to have kids unless I can get this cured. But if this works, it means I could start a family one day.”
You can learn more about Evie’s story and the remarkable CIRM funded work at UCLA by watching the video below.
Leukocyte Adhesion Deficiency-I (LAD-I) is a rare pediatric disease caused by a mutation in a specific gene that causes low levels of a protein called CD18. Due to low levels of CD18, the adhesion of immune cells is affected, which negatively impacts the body’s ability to combat infections.
Rocket Pharmaceuticals has announced positive results from a CIRM-funded clinical trial that is testing a treatment that uses a gene therapy called RP-L201. The therapy uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.
The two patients enrolled in the CIRM funded trial have shown restored levels of CD18. Previous studies have indicated that an increase in CD18 to 4-10% is associated with survival into adulthood. The two patients demonstrated CD18 levels that exceeded this threshold.
In a news release, Jonathan Schwartz, M.D. Chief Medical Officer and Senior Vice President of Rocket, elaborated on these positive results.
“Patients with LAD-I have markedly diminished expression of the integrin CD18 and suffer from life-threatening bacterial and fungal infections. Natural history studies indicate that an increase in CD18 expression to 4-10% is associated with survival into adulthood. The two patients enrolled in our Phase 1 trial demonstrated restored CD18 expression substantially exceeding this threshold. In addition, we continue to observe a durable treatment effect in the patient followed through one year, with improvement of multiple disease-related skin lesions after therapy and no further requirements for prophylactic anti-infectives.”
A simple blood stem cell transplant is showing tremendous promise in treating a wide range of metabolic, blood and immune disorders such as thalassemia and some leukodystrophies.
These are considered rare diseases – meaning there are fewer than 200,000 people with them in the US – so there is often little funding available to develop new therapies to help people suffering from them. So, researchers at UPMC Children’s Hospital of Pittsburgh set out to develop a therapy that could help several different disorders without having to craft individual approaches for each condition.
The team used blood stem cells from donated umbilical cords and placentas. In a news article, study senior author Dr. Paul Szabolcs, said they then used a combination of chemotherapy and immunotherapy to prepare the patients for the transplant and increase the chance of success.
“We approached the topic with the mindset to design a regimen that carefully balances low-intensity chemo (bringing safety) with sufficiently effective immunotherapy to blast away the patients’ immune system, therefore preventing rejection. Rejection has been a common failure when other centers explored the reduced-intensity conditioning (RIC) approach with cord blood. We are the first to prove the RIC is able to give reliable results in long-term engraftment.”
Szabolcs says another advantage to their approach was that it meant there didn’t need to be a perfect immune system match of donor and recipient.
“That’s huge for ethnic minorities. The probability of a perfect match is very low, but with a cord blood graft, we have a chance to overcome this discrepancy over the course of a couple months and then taper immunosuppressants away.”
Altogether 44 children were treated this way. After undergoing the preparation, they had the blood stem cells transfused into them and, once those cells had integrated into the body they got a second, smaller, transfusion a few weeks later to help kick start their immune system.
Most of the complications from the infusions were mild, and while around 5 percent of children died from viral infection due to the immune suppression this was much lower than in earlier studies. Another encouraging sign was that none of the children suffered severe Graft vs Host disease which can be fatal.
Thirty of the children in the trial suffered from metabolic disorders, meaning their bodies were unable to remove dangerous toxins, and this led to developmental delays in their brains. One year after the treatment all 30 children had normal enzyme levels and their neurological decline had stopped. Some of the children even showed improvements and gained new skills.
Most of the children with metabolic disorders had leukodystrophies. These are usually fatal within a few years of diagnosis. Even with a cord blood transplant the three-year survival rate is only 60 percent. In this trial more than 90 percent of children with leukodystrophies were alive after three years.
Dr. Szabolcs says this approach has a lot of advantages over existing approaches, including cost.
“There has been a lot of emphasis placed on cool new technologies that might address these diseases, but — even if they prove effective — those aren’t available to most centers. The regimen we developed is more robust, readily applicable and will remain significantly less expensive.”
Image of the virus that causes AIDS – courtesy NIH
If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?
First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.
Dr. Scott Kitchen: Photo David Geffen School of Medicine, UCLA
UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.
Dr. Irvin Chen: Photo UCLA
Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.
That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.
In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”
By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.
The Stem Cellar 