CIRM funded trial for LAD-I announces positive results

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.”

Cord blood transplants help children fighting deadly diseases

Dr. Paul Szabolcs: Photo courtesy of UPMC

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.”

The study was published in the journal Blood Advances.

Scientists Engineer Stem Cells to Fight HIV

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.

CIRM has already funded three clinical trials targeting HIV/AIDS. Two of these are still active; Dr. Mehrdad Abedi at UC Davis and Dr. John Zaia at City of Hope.

Novel clinical trial for COVID-19 using immune cells

This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab.
Image Credit: National Institute of Allergy and Infectious DiseasesRocky Mountain Laboratories

During this global pandemic, many scientists are pursuing various avenues for potential treatments of COVID-19.  The Infectious Disease Research Institute (IDRI), in collaboration with Celularity Inc., will conduct a clinical trial with 100 patients using an immunotherapy for treatment of COVID-19.

The treatment will involve administering specialized immune cells called Natural Killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system. Previously, these cells have been administered in early safety studies to treat patients with blood cancers. NK cells play an important role in fighting off viral infections. In initial patients with severe cases of COVID-19, low NK cell counts were observed.

The NK cells used in this study are derived from blood stem cells obtained from the placenta. They will be administered to patients diagnosed with a COVID-19 infection causing pneumonia.

In a press release, IDRI’s CEO Corey Casper talks in more detail about how the NK cells could help treat patients with COVID-19.

“The hypothesis is that administering NK cells to patients with moderate to severe COVID-19 will allow the immune cells find the sites of active viral infection, kill the virus, and induce a robust immune response that will help heal the damage and control the infection.”

In the same press release, Corey Casper also mentions the other applications this treatment could have.

“Beyond its promise as a critically needed treatment for COVID-19, the biology of NK cells indicates a possibility that this immunotherapy could be used as an off-the-shelf treatment for future pandemic infections.”

Breakthrough image could lead to better therapies

Image of a blood stem cell in its natural environment: Photo courtesy UC Merced

When it comes to using stem cells for therapy you don’t just need to understand what kinds of cell to use, you also need to understand the environment that is best for them. Trying to get stem cells to grow in the wrong environment would be like trying to breed sheep in a pond. It won’t end well.

But for years scientists struggled to understand how to create the right environment, or niche, for these cells. The niche provides a very specific micro-environment for stem cells, protecting them and enabling them to self-renew over long periods of time, helping repair damaged tissues and organs in the body.

But different stem cells need different niches, and those involve both physical and chemical properties, and getting that mixture right has been challenging. That in turn has slowed down our ability to use those cells to develop new therapies.

UC Merced’s Joel Spencer in the lab: Photo courtesy UC Merced

Now UC Merced’s Professor Joel Spencer and his team have developed a way of capturing an image of hematopoietic or blood stem cells (HSCs), inside their niche in the bone marrow. In an article on UC Merced News, he says this could be a big step forward.

“Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment. It’s analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment.

“This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.”

In the past, studying HSCs involved transplanting them into a mouse or other animal that had undergone radiation to kill off its own bone marrow cells. It enabled researchers to track the HSCs but clearly the new environment was very different than the original, natural one. So, Spencer and his team developed new microscopes and imaging techniques to study cells and tissues in their natural environment.  

In the study, published in the journal Nature, Spencer says all this is only possible because of recent technological breakthroughs.

“My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades. You need to be able to peer inside an organ, inside a live animal and see what’s happening as it happens.”

Being able to see how these cells behave in their natural environment may help researchers learn how to recreate that environment in the lab, and help them develop new and more effective ways of using those cells to repair damaged tissues and organs.

Researchers create a better way to grow blood stem cells

UCLA’s Dr. Hanna Mikkola and Vincenzo Calvanese, lead scientists on the study. Photo courtesy UCLA

Blood stem cells are a vital part of us. They create all the other kinds of blood cells in our body and are used in bone marrow transplants to help people battling leukemia or other blood cancers. The problem is growing these blood stem cells outside the body has always proved challenging. Up till now.

Researchers at UCLA, with CIRM funding, have identified a protein that seems to play a key role in helping blood stem cells renew themselves in the lab. Why is this important? Because being able to create a big supply of these cells could help researchers develop new approaches to treating a wide array of life-threatening diseases.

One of the most important elements that a stem cell has is its ability to self-renew itself over long periods of time. The problem with blood stem cells has been that when they are removed from the body they quickly lose their ability to self-renew and die off.

To discover why this is the case the team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA analyzed blood stem cells to see which genes turn on and off as those cells turn into other kinds of blood cells – red, white and platelets. They identified one gene, called MLLT3, which seemed to play a key role in helping blood stem cells self-renew.

To test this finding, the researchers took blood stem cells and, in the lab, inserted copies of the MLLT3 gene into them. The modified cells were then able to self-renew at least 12 times; a number far greater than in the past.

Dr. Hanna Mikkola, a senior author of the study says this finding could help advance the field:

“If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number. But we’re not just focusing on quantity; we also need to ensure that the lab-created blood stem cells can continue to function properly by making all blood cell types when transplanted.”

Happily, that seemed to be the case. When they subjected the MLLT3-enhanced blood stem cells to further analysis they found that they appeared to self-renew at a safe rate and didn’t multiply too much or mutate in ways that could lead to leukemia or other blood cancers.

The next steps are to find more efficient and effective ways of keeping the MLLT3 gene active in blood stem cells, so they can develop ways of using this finding in a clinical setting with patients.

Their findings are published in the journal Nature.

Boosting the blood system after life-saving therapy

Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA

Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.

First a little background. Some cancer treatments use chemotherapy and radiation to kill the cancer, but they can also damage other cells, including those in the bone marrow responsible for making blood stem cells. Those cells eventually recover but it can take weeks or months, and during that time the patient may feel fatigue and be more susceptible to infections and other problems.

In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.

They focused their attention on a protein called PTP-sigma that is found in blood stem cells and acts as a kind of brake on the regeneration of those cells. Previous studies by Dr. Chute showed that, after undergoing radiation, mice that have less PTP-sigma were able to regenerate their blood stem cells faster than mice that had normal levels of the protein.

John Chute: Photo courtesy UCLA

So they set out to identify something that could help reduce levels of PTP-sigma without affecting other cells. They first identified an organic compound with the charming name of 6545075 (Chembridge) that was reported to be effective against PTP-sigma. Then they searched a library of 80,000 different small molecules to find something similar to 6545075 (and this is why science takes so long).

From that group they developed more than 100 different drug candidates to see which, if any, were effective against PTP-sigma. Finally, they found a promising candidate, called DJ009. In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in human blood stem cells.

They then tested DJ009 in mice that were given high doses of radiation. In a news release Dr. Chute said the results were very encouraging:

“The potency of this compound in animal models was very high. It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Of the radiated mice, most that were given DJ009 survived. In comparison, those that didn’t get DJ009 died within three weeks.

They saw similar benefits in mice given chemotherapy. Mice with DJ009 saw their white blood cells – key components of the immune system – return to normal within two weeks. The untreated mice had dangerously low levels of those cells at the same point.

It’s encouraging work and the team are already getting ready for more research so they can validate their findings and hopefully take the next step towards testing this in people in clinical trials.

CIRM Board Approves New Clinical Trial for Rare Childhood Disease

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved a grant of almost $12 million to Dr. Stephanie Cherqui at the University of California, San Diego (UCSD) to conduct a clinical trial for treatment of cystinosis.

This award brings the total number of CIRM funded clinical trials to 55. 

Cystinosis is a rare disease that primarily affects children and young adults, and leads to premature death, usually in early adulthood.  Patients inherit defective copies of a gene called CTNS, which results in abnormal accumulation of an amino acid called cystine in all cells of the body.  This buildup of cystine can lead to multi-organ failure, with some of earliest and most pronounced effects on the kidneys, eyes, thyroid, muscle, and pancreas.  Many patients suffer end-stage kidney failure and severe vision defects in childhood, and as they get older, they are at increased risk for heart disease, diabetes, bone defects, and neuromuscular defects.  There is currently a drug treatment for cystinosis, but it only delays the progression of the disease, has severe side effects and is expensive.

Dr. Cherqui’s clinical trial will use a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. Based on pre-clinical data, the approach is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.  

Because this is the first time this approach has been tested in patients, the primary goal of the clinical trial is to see if the treatment is safe.  In addition, patients will be monitored for improvements in the symptoms of their disease.  This award is in collaboration with the University of California, Los Angeles which will handle the manufacturing of the therapy.

CIRM has also funded the preclinical work for this study, which involved completing the testing needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial in people.

“CIRM has funded 24 clinical stage programs utilizing cell and gene medicine approaches to date,” says Maria T. Millan, M.D., the President and CEO of CIRM.  “This project continues to broaden the scope of unmet medical need we can impact with these types of approaches.”

Stanford study successful in transplant of mismatched stem cells, tissue in mice

Dr. Irv Weissman at Stanford University

A transplant can be a lifesaving procedure for many people across the United States. In fact, according to the Health Resources & Services Administration, 36,528 transplants were performed in 2018. However, as of January 2019, the number of men, women, and children on the national transplant waiting list is over 113,000, with 20 people dying each day waiting for a transplant and a new person being added to the list every 10 minutes.

Before considering a transplant, there needs to be an immunological match between the donated tissue and/or blood stem cells and the recipient. To put it simply, a “match” indicates that the donor’s cells will not be marked by the recipient’s immune cells as foreign and begin to attack it, a process known as graft-versus-host disease. Unfortunately, these matches can be challenging to find, particularly for some ethnic minorities. Often times, immunosuppression drugs are also needed in order to prevent the foreign cells from being attacked by the body’s immune system. Additionally, chemotherapy and radiation are often needed as well.

Fortunately, a CIRM-funded study at Stanford has shown some promising results towards addressing the issue of matching donor cells and recipient. Dr. Irv Weissman and his colleagues at Stanford have found a way to prepare mice for a transplant of blood stem cells, even when donor and recipient are an immunological mismatch. Their method involved using a combination of six specific antibodies and does not require ongoing immunosuppression.

The combination of antibodies did this by eliminating several types of immune cells in the animals’ bone marrow, which allowed blood stem cells to engraft and begin producing blood and immune cells without the need for continued immunosuppression. The blood stem cells used were haploidentical, which, to put it simply, is what naturally occurs between parent and child, or between about half of all siblings. 

Additional experiments also showed that the mice treated with the six antibodies could also accept completely mismatched purified blood stem cells, such as those that might be obtained from an embryonic stem cell line. 

The results established in this mouse model could one day lay the foundation necessary to utilize this approach in humans after conducting clinical trials. The idea would be that a patient that needs a transplanted organ could first undergo a safe, gentle transplant with blood stem cells derived in the laboratory from embryonic stem cells. The same embryonic stem cells could also then be used to generate an organ that would be fully accepted by the recipient without requiring the need for long-term treatment with drugs to suppress the immune system. 

In a news release, Dr. Weissman is quoted as saying,

“With support by the California Institute for Regenerative Medicine, we’ve been able to make important advances in human embryonic stem cell research. In the past, these stem cell transplants have required a complete match to avoid rejection and reduce the chance of graft-versus-host disease. But in a family with four siblings the odds of having a sibling who matches the patient this closely are only one in four. Now we’ve shown in mice that a ‘half match,’ which occurs between parents and children or in two of every four siblings, works without the need for radiation, chemotherapy or ongoing immunosuppression. This may open up the possibility of transplant for nearly everyone who needs it. Additionally, the immune tolerance we’re able to induce should in the future allow the co-transplantation of [blood] stem cells and tissues, such as insulin-producing cells or even organs generated from the same embryonic stem cell line.”

The full results to this study were published in Cell Stem Cell.

Stanford and University of Tokyo researchers crack the code for blood stem cells

Blood stem cells grown in lab

Blood stem cells offer promise for a variety of immune and blood related disorders such as sickle cell disease and leukemia. Like other stem cells, blood stem cells have the ability to generate additional blood stem cells in a process called self-renewal. Additionally, they are able to generate blood cells in a process called differentiation. These newly generated blood cells have the potential to be utilized for transplantations and gene therapies.

However, two limitations have hindered the progress made in this field. One problem relates to the amount of blood stem cells needed to make a potential transplantation or gene therapy viable. Unfortunately, it has been challenging to isolate and grow blood stem cells in large quantity needed for these approaches. A part of this reason relates to getting the blood stem cells to self-renew rather than differentiate.

The second problem involves the existing blood stem cells in the patient’s body prior to transplantation. In order for the procedure to work, the patient’s own blood stem cells must be eliminated to make space for the transplanted blood stem cells. This is done through a process known as conditioning, which typically involves chemotherapy and/or radiation. Unfortunately, chemotherapy and radiation can cause life-threatening side effects due to its toxicity, particularly in pediatric patients, such as growth retardation, infertility and secondary cancer in later life. Very sick or elderly patients are unable to tolerate this conditioning process, making them ineligible for transplants.

A CIRM funded study by a team at Stanford and the University of Tokyo has unlocked the code related to the generation of blood stem cells.

The collaborative team was able to modify the components used to grow blood stem cells. By making these modifications, which effects the growth and physical conditions of blood stem cells, the researchers have shown for the first time that it’s possible to get blood stem cells from mice to renew themselves hundreds or even thousands of times within a period of just 28 days. 

Furthermore, the team showed that when they transplanted the newly grown cells into mice that had not undergone conditioning, the donor cells had engrafted and remained functional.

The team also found that gene editing technology such as CRISPR could be used while growing an adequate supply of blood stem cells for transplantation. This opens the possibility of obtaining a patient’s own blood stem cells, correcting the problematic gene, and reintroducing these back to the patient.

The complete study was published in Nature.

In a news release, Dr. Hiromitsu Nakauchi, a senior author of the study, is quoted as saying,

“For 50 years, researchers from laboratories around the world have been seeking ways to grow these cells to large numbers. Now we’ve identified a set of conditions that allows these cells to expand in number as much as 900-fold in just one month. We believe this approach could transform how [blood] stem cell transplants and gene therapy are performed in humans.”