UCSD researchers use stem cell model to better understand pregnancy complication

A team of UC San Diego researchers recently published novel preeclampsia models to aid in understanding this pregnancy complication that occurs in one of 25 U.S. pregnancies. Researchers include (left to right): Ojeni Touma, Mariko Horii, Robert Morey and Tony Bui. Credit: UC San Diego

Pregnant women often tread uncertain waters in regards to their health and well-being as well as that of their babies. Many conditions can arise and one of these is preeclampsia, a type of pregnancy complication that occurs in approximately one in 25 pregnancies in the United States according to the Center for Disease Control (CDC). It occurs when expecting mothers develop high blood pressure, typically after 20 weeks of pregnancy, and that in turn reduces the blood supply to the baby. This can lead to serious, even fatal, complications for both the mother and baby.

A CIRM supported study using induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any cell type, was able to create a “disease in a dish” model in order to better understand preeclampsia.

Credit: UC San Diego

For this study, Mariko Horii, M.D., and her team of researchers at the UC San Diego School of Medicine obtained cells from the placenta of babies born under preeclampsia conditions. These cells were then “reprogrammed” into a stem cell-like state, otherwise known as iPSCs. The iPSCs were then turned into cells resembling placental cells in early pregnancy. This enabled the team to create the preeclampsia “disease in the dish” model. Using this model, they were then able to study the processes that cause, result from, or are otherwise associated with preeclampsia.

The findings revealed that cellular defects observed are related to an abnormal response in the environment in the womb. Specifically, they found that preeclampsia was associated with a low-oxygen environment in the uterus. The researchers used a computer modeling system at UC San Diego known as Comet to detail the differences between normal and preeclampsia placental tissue.

Horii and her team hope that these findings not only shed more light on the environment in the womb observed in preeclampsia, but also provided insight for future development of diagnostic tools and identification of potential medications. Furthermore, they hope that their iPSC disease model can be used to study other placenta-associated pregnancy disorders such as fetal growth restriction, miscarriage, and preterm birth.

The team’s next steps are to develop a 3D model to better study the relationship between environment and development of placental disease.

In a news release from UC San Diego, Horri elaborates more on these future goals.

“Currently, model systems are in two-dimensional cultures with single-cell types, which are hard to study as the placenta consists of maternal and fetal cells with multiple cell types, such as placental cells (fetal origin), maternal immune cells and maternal endometrial cells. Combining these cell types together into a three-dimensional structure will lead to a better understanding of the more complex interactions and cell-to-cell signaling, which can then be applied to the disease setting to further understand pathophysiology.”

The full study was published in Scientific Reports.

CIRM funded trial may pave way for gene therapy to treat different diseases

Image Description: Jordan Janz (left) and Dr. Stephanie Cherqui (right)

According to the  National Organization for Rare Disorders (NORD), a disease is consider rare if it affects fewer than 200,000 people. If you combine the over 7,000 known rare diseases, about 30 million people in the U.S. are affected by one of these conditions. A majority of these conditions have no cure or have very few treatment options, but a CIRM funded trial (approximately $12 million) for a rare pediatric disease has showed promising results in one patient using a gene therapy approach. The hope for the field as a whole is that this proof of concept might pave the way to use gene therapy to treat other diseases.

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 that results in abnormal accumulation of cystine (hence the name cystinosis) 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 problems.  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. Stephane Cherqui at UC San Diego (UCSD), in partnership with AVROBIO, is conducting a clinical trial that uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective gene. The corrected stem cells are then reintroduced into the patient with the hope that they will give rise to blood cells that will reduce cystine buildup in the body.  

22 year old Jordan Janz was born with cystinosis and was taking anywhere from 40 to 60 pills a day as part of his treatment. Unfortunately the medication affected his body odor, leaving him smelling like rotten eggs or stinky cheese. In 2019, Jordan was the first of three patients to participate in Dr. Cherqui’s trial and the results have been remarkable. Tests have shown that the cystine in his eyes, skin and muscle have greatly decreased. Instead of the 40-60 pills a day, he just takes vitamins and specific nutrients his body needs. What’s more is that he no longer has a problem with body odor caused by the pills he once had to take. Although it will take much more time know if Jordan was cured of the disease, he says that he feels “essentially cured”.

In an article from the Associated Press, Jordan is optimistic about his future.

“I have more of a life now. I’m going to school. I’m hoping to open up my own business one day.”

You can learn more about Jordan by watching the video below:

Although gene therapy approaches still need to be closely studied, they have enormous potential for treating patients. CIRM has funded other clinical trials that use gene therapy approaches for different genetic diseases including X-SCID, ADA-SCID, ART-SCID, X-CGD, and sickle cell disease.

Study shows connection between bipolar disorder and neuroinflammation

Astrocytes, which provide structural support and protection for neurons and also supply them with nutrients and oxygen.

Bipolar disorder (BPD) is a mental disorder that causes unusual shifts in mood, energy, activity levels, concentration, and the ability to carry out day-to-day tasks. In the United States, recent research has shown that 1.6% of the population has BPD, which is roughly over 4 million people. Those with BPD are more likely to have conditions associated with chronic inflammation such as hypertension and diabetes. It is because of this that scientists have been studying the connection between inflammation and BPD for quite some time.

In a new study, researchers at the Salk Institute for Biological Studies, UC San Diego, and the Institute of Psychiatry and Neuroscience of Paris have found evidence that astrocytes, a certain type of brain cell, can trigger inflammation more easily in those that have BPD. What’s more, these astrocytes can be linked to decreased brain activity that could be harmful to mental health.

Astrocytes are star shaped (as the word “astro” might suggest) and help support neurons, the cells that relay information around the brain. One of these supporting roles includes helping trigger inflammation in the brain and the surrounding nervous system to help with injury or infection. The researchers believe that this process can go wrong in people with BPD and that astrocytes can play a role in this dysfunctional inflammation.

For this study, the team used induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any type of cell, that they created from patients with BPD and patients without BPD. They converted these iPSCs into astrocytes and compared those that came from BPD patients to those that did not. What they found is that the astrocytes from patients with BPD were noticeably different. The BPD astrocytes had a higher expression of a protein that triggers an inflammatory response when compared to the non-BPD astrocytes. When they exposed neurons to the BPD astrocytes, the team saw decreased levels of neural activity compared to the non-BPD astrocytes. Lastly, when the researchers blocked the inflammatory protein, the neurons were less affected by the BPD astrocytes.

“Our study suggests that normal function of astrocytes is affected in bipolar disorder patients’ brains, contributing to neuroinflammation,” said Dr. Renata Santos, a researcher at the Salk Institute as well as the Institute of Psychiatry and Neuroscience of Paris, in a news release.

The team hopes that their findings can not only provide insight into BPD, but to other mental illnesses linked to inflammation such as schizophrenia. The ultimate goal is to help advance research into astrocytes and inflammation in order to develop treatments that might reverse the harmful bodily changes seen in those with BPD and other mental disorders.

The full study was published in Stem Cell Reports.

Scientists look at how the lung and brain respond differently to SARS-CoV-2 infection

UC San Diego School of Medicine researchers found approximately 10-fold higher SARS-CoV-2 infection (green) in lung organoids (left), compared to brain organoids (right). Image courtesy of UCSD Health

Since the start of the coronavirus pandemic early last year, scientists all over the world are still trying to better understand SARS-CoV-2, the virus that causes COVID-19. Although the more commonly known symptoms involve respiratory issues, there have been other long term problems observed in recovered patients. These consist of heart issues, fatigue, and neurological issues such as loss of taste and smell and “brain fog”.

To better understand this, Dr. Tariq Rana and a team of researchers at the UC San Diego School of Medicine are using stem cells to create lung and brain organoids to better understand how the virus interacts with the various organ systems and to better develop therapies that block infection. Organoids are 3D models made of cells that can be used to analyze certain features of the human organ being modeled. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. 

The team’s lung and brain organoids produced molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 is able to use these doorknobs to enter cells and establish infection.

Dr. Rana and his team then developed a pseudovirus, a noninfectious version of SARS-CoV-2, and attached a fluorescent label, allowing them to measure how effectively the virus binds in human lung and brain organoids as well as to evaluate the cells’ response. The team was surprised to see an approximately 10-fold higher SARS-CoV-2 infection in lung organoids compared to brain organoids. Additionally, treatment with TMPRSS2 inhibitors reduced infection levels in both organoids.

Besides differences in infection levels, the lung and brain organoids also differed in their responses to the virus. Infected lung organoids pumped out molecules intended to summon help from the immune system while infected brain organoids upped their production of molecules that plays a fundamental role in pathogen recognition and activation of the body’s own immune defenses.

In a news release from UC San Diego Health, Dr. Rana elaborates on the results of his study.

“We’re finding that SARS-CoV-2 doesn’t infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes.”

The next steps for Rana and his team is to develop SARS-CoV-2 inhibitors and test out how well they work in organoid models derived from people of a variety of racial and ethnic backgrounds that represent California’s diverse population. To carry out this research, CIRM awarded Dr. Rana a grant of $250,000, which is part of the $5 million in emergency funding for COVID-19 research that CIRM authorized at the beginning of the pandemic.

The full results of this study can be found in Stem Cell Reports.

U.C. San Diego Scientist Larry Goldstein Joins Stem Cell Agency’s Board

Larry Goldstein, PhD.

Larry Goldstein PhD, has many titles, one of which sums up his career perfectly, “Distinguished Professor”. Dr. Goldstein has distinguished himself on many fronts, making him an ideal addition to the governing Board of the California Institute for Regenerative Medicine (CIRM).

Dr. Goldstein – everyone calls him Larry – is a Cell Biologist, Geneticist and Neuroscientist. He worked with many colleagues to launch the UC San Diego Stem Cell program, the Sanford Consortium for Regenerative Medicine and the Sanford Stem Cell Clinical Center. He has received the Public Service Award from the American Society for Cell Biology and has had a Public Policy Fellowship named for him by the International Society for Stem Cell Research. He is a member of the American Academy of Arts and Sciences and last year was named a member of the prestigious National Academy of Sciences.

“I look forward to working with the ICOC and CIRM staff to ensure that the best and most promising stem cell research and medicine is fostered and funded,” Larry said.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

He was appointed to the CIRM Board by Pradeep Khosla, the Chancellor of U.C. San Diego saying he is “gratified you are assuming this important role.”

Jonathan Thomas, JD, PhD., Chair of the CIRM Board, welcome the appointment saying “I have known Larry for many years and have nothing but the highest regard for him as a scientist, a leader, and a great champion of stem cell research. He is also an innovative thinker and that will be invaluable to us as we move into a second chapter in the life of CIRM.”

Larry was born in Buffalo, New York and grew up in Thousand Oaks, California. He graduated from UC San Diego with a degree in Biology in 1976 and from the University of Washington with a Ph. D. in Genetics in 1980. He joined the faculty in Cell and Developmental Biology at Harvard University in 1984 where he was promoted to Full Professor with tenure in 1990. He returned to UC San Diego and the Howard Hughes Medical Institute in 1993. After 45 years pursuing cutting edge lab-based research Larry is now transitioning to an administrative and executive role at UC San Diego where he will serve as the Senior Advisor for Stem Cell Research and Policy to the Vice Chancellor of Health Sciences.

He replaces David Brenner who is standing down after completing two terms on the Board.

De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

DNA therapeutic treats blood cancer in mice and begins human clinical trial

The left image represents a microscopic view of the bone marrow of a myeloma-bearing mouse treated with control, and the right image represents the same for a myeloma-bearing mouse treated with ION251, an experimental therapeutic. The red dots represent the IRF4 protein within human myeloma cells, which are much sparser after ION251 treatment. Image credit: UC San Diego Health

Multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020.  Unfortunately, many patients with this type of blood cancer eventually develop resistance to multiple types of treatments.  This phenomenon is partially due to the fact that cancer stem cells, which have the ability to evade traditional therapies and then self-renew, help drive the disease.

It is for this reason that a team of researchers, at the UC San Diego School of Medicine and Ionis Pharmaceuticals, are developing a therapy that can destroy these malignant stem cells, thereby preventing the cancer from coming back.  With support from CIRM, the team developed an approach that interacts with IRF4, a gene that allows myeloma stem cells and tumor cells to grow and survive chemotherapy and radiation.  They have engineered an oligonucleotide, a short DNA molecule, to prevent IRF4 from functioning.  The therapy, known as ION251, lowered disease burden, reduced the amount of myeloma stem cells, and increased survival when tested in mice bearing human myeloma.  These results have enabled the team to start a Phase I clinical trial to see if this approach is safe and effective in people with myeloma.

To study the disease and test ION251, the team transplanted human myeloma cells into mice that lack an immune system and thus won’t reject human cells.  Ten mice received the ION251 treatment and an additional ten mice received a control treatment.  After receiving the ION251 therapy, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment.  Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did. 

In a news release from UC San Diego Health, Dr. Leslie Crews, co-senior author and assistant professor at the UCSD School of Medicine, elaborated on the promising results from the mouse study.

“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study.  It makes the science more difficult, but it gives me hope for patients.”

The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information on this can be viewed by clicking the link here.

The full results of this study were published in the journal Cell Stem Cell.

“Mini-brains” model an autism spectrum disorder and help test treatments

Alysson Muotri, PhD, professor and director of the Stem Cell Program at UC San Diego School of Medicine
and member of the Sanford Consortium for Regenerative Medicine.
Image credit: UC San Diego Health

Rett syndrome is a rare form of autism spectrum disorder that impairs brain development and causes problems with movement, speech, and even breathing. It is caused by mutations in a gene called MECP2 and primarily affects females. Although there are therapies to alleviate symptoms, there is currently no cure for this genetic disorder.

With CIRM funding ($1.37M and $1.65M awards), Alysson Muotri, PhD and a team of researchers at the University of California San Diego School of Medicine and Sanford Consortium for Regenerative Medicine have used brain organoids that mimic Rett syndrome to identify two drug candidates that returned the “mini-brains” to near-normal. The drugs restored calcium levels, neurotransmitter production, and electrical impulse activity.

Brain organoids, also referred to as “mini-brains”, are 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study changes in physical structure or gene expression over time.

Dr. Muotri and his team created induced pluripotent stem cells (iPSCs), a type of stem cell that can become virtually any type of cell. For the purposes of this study, they were created from the skin cells of Rett syndrome patients. The newly created iPSCs were then turned into brain cells and used to create “mini-brains”, thereby preserving each Rett syndrome patient’s genetic background. In addition to this, the team also created “mini-brains” that artificially lack the MECP2 gene, mimicking the issues with the same gene observed in Rett syndrome.

Lack of the MECP2 gene changed many things about the “mini-brains” such as shape, neuron subtypes present, gene expression patterns, neurotransmitter production, and decreases in calcium activity and electrical impulses. These changes led to major defects in the emergence of brainwaves.

To correct the changes caused by the lack of the MECP2 gene, the team treated the brain organoids with 14 different drug candidates known to affect various brain cell functions. Of all the drugs tested, two stood out: nefiracetam and PHA 543613. The two drugs resolved nearly all molecular and cellular symptoms observed in the Rett syndrome “mini-brains”, with the number active neurons doubling post treatment.

The two drugs were previously tested in clinical trials for the treatment of other conditions, meaning they have been shown to be safe for human consumption.

In a news release from UC San Diego Health, Dr. Muotri stresses that although the results for the two drugs are promising, the end treatment for Rett syndrome may require a multi-drug cocktail of sorts.

“There’s a tendency in the neuroscience field to look for highly specific drugs that hit exact targets, and to use a single drug for a complex disease. But we don’t do that for many other complex disorders, where multi-pronged treatments are used. Likewise, here no one target fixed all the problems. We need to start thinking in terms of drug cocktails, as have been successful in treating HIV and cancers.”

The full results of this study were published in EMBO Molecular Medicine.

Charting a new course for stem cell research

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

CIRM Board Approves Two New Discovery Research Projects for COVID-19

Dr. Karen Christman (left) and Dr. Lili Yang (right)

This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two new discovery research project as part of the $5 million in emergency funding for COVID-19 related projects.  This brings the number of COVID-19 projects CIRM is supporting to 17, including three clinical trials.

$249,974 was awarded to Dr. Karen Christman at UC San Diego to develop a treatment for Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung injury that occurs when fluid leaks into the lungs and is prevalent in COVID-19 patients.  Dr. Christman and her team will develop extracellular matrix (ECM) hydrogels, a kind of structure that provides support to surrounding cells.  The goal is to develop a treatment that can be delivered directly to site of injury, where the ECM would recruit stem cells, treat lung inflammation, and promote lung healing.

$250,000 was awarded to Dr. Lili Yang at UCLA to develop a treatment for COVID-19.  Dr. Yang and her team will use blood stem cells to create invariant natural killer T (iNKT) cells, a powerful kind of immune cell with the potential to clear virus infection and mitigate harmful inflammation.  The goal is to develop these iNKT cells as an off the shelf therapy to treat patients with COVID-19.

These awards are part of CIRM’s Quest Awards Program (DISC2), which promotes promising new technologies that could be translated to enable broad use and improve patient care.

“The harmful lung inflammation caused by COVID-19 can be dangerous and life threatening,” says Maria T. Millan, M.D., the President and CEO of CIRM. “Early stage discovery projects like the ones approved today are vital in developing treatments for patients severely affected by the novel coronavirus.”

Earlier in the week the Board also approved changes to both DISC2 and clinical trial stage projects (CLIN2). These were in recognition of the Agency’s remaining budget and operational timeline and the need to launch the awards as quickly as possible.

For DISC2 awards the changes include:

  • Award limit of $250,000
  • Maximum award duration of 12 months
  • Initiate projects within 30 days of approval
  • All proposals must provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity.
  • All proposals should discuss the limitations, advantages, and/or challenges in developing a product or tools that addresses the unmet medical needs of California’s diverse population, including underserved communities.

Under the CLIN2 awards, to help projects carry out a clinical trial, the changes include:

  • Adjust award limit to the following:
Applicant typePhase 1, Phase 1/2, Feasability Award CapPhase 2 Award CapPhase 3 Award Cap
Non-profit$9M$11.25M$7.5M
For-profit$6M$11.25M$7.5M
  • Adjust the award duration to not exceed 3 years with award completion no later than November 2023
  • Initiate projects within 30 days of approval
  • All proposals must include a written plan in the application for outreach and study participation by underserved and disproportionately affected populations. Priority will be given to projects with the highest quality plans in this regard.

The changes outlined above for CLIN2 awards do not apply to sickle cell disease projects expected to be funded under the CIRM/NHLBI Cure Sickle Cell Disease joint Initiative.