World Sickle Cell Day: A View from the Front Line

June 19th is World Sickle Cell Day. Sickle cell disease is an inherited blood disorder that causes normally round red blood cells to take on an abnormal sickle shape, resulting in clogged arteries, severe pain, increased risk of stroke and reduced life expectancy. To mark the occasion we asked Nancy M. Rene to write a guest blog for us. Nancy is certainly qualified; she is the grandmother of a child with sickle cell disease, and the co-founder of Axis Advocacy, a non-profit advocating for those with sickle cell disease and their families.

Nancy ReneOn this World Sickle Cell Day, 2017, we can look back to the trailblazers in the fight against Sickle Cell Disease.  More than 40 years ago, the Black Panther Party established the People’s Free Medical Clinics in several cities across the country. One of the functions of these free clinics: to screen people for sickle cell disease and sickle cell trait. This life-saving screening began  in 1971.

Around that same time, President Richard Nixon allocated $10 million to begin the National Sickle Cell Anemia Control Act. This included counseling and screening, educational activities, and money for research.

In the early part of the twentieth century, most children with sickle cell died before their fifth birthday. With newborn screening available nationwide, the use of penicillin to prevent common infections, and the finding that hydroxyurea was useful in fighting the disease, life expectancy began to improve.

For much of the twentieth century, people with sickle cell disease felt that they were fighting the fight alone, knowledgeable doctors were scarce and insurance was often denied.

Making progress

As we moved into the twenty-first century, patients and families found they had some powerful allies. The National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) joined the battle.  In 2016 the NIH held its tenth annual international conference on sickle cell disease that featured speakers from all over the world.  Participants were able to learn about best practices in Europe, Africa, India, and South America.

Sickle Cell centers at Howard University, the Foundation for Sickle Cell Disease Research, and other major universities across the country are pointing the way to the best that medicine has to offer.

Last year, the prestigious American Society of Hematology (ASH) launched an initiative to improve understanding and treatment of sickle cell disease.  Their four-point plan includes education, training, advocacy, and expanding its global reach.

Just last month, May 2017, the FDA looked at Endari, developed by Emmaus Medical in Torrance, California.  It is the first drug specifically developed for sickle cell disease to go through the FDA’s approval process. We should have a decision on whether or not the drug goes to market in July.

The progress that had been made up to the beginning of the twenty-first century was basically about alleviating the symptoms of the disease: the sickling, the organ damage and the pervasive anemia. But a cure was still elusive.

But in 2004, California’s Stem Cell Agency, CIRM, was created and it was as if the gates had opened.

Researchers had a new source of funding to enable  them to work on Sickle Cell Disease and many other chronic debilitating diseases at the cellular level. Scientists like Donald Kohn at UCLA, were able to research gene editing and find ways to use autologous bone marrow transplants to actually cure people with sickle cell. While some children with sickle cell have been cured with traditional bone marrow transplants, these transplants must come from a matched donor, and for most patients, a matched donor is simply not available. CIRM has provided the support needed so that researchers are closing in on the cure. They are able to share strategies with doctors and researchers throughout the world

And finally, support from the federal government came with the passage of the Affordable Care Act and adequate funding for the NIH, CDC, the Health Resources and Services Administration (HRSA), and FDA.

Going backwards

And yet, here we are, World Sickle Cell Day, 2017.

Will this be a case of one step forward two steps back?

Are we really going back to the time when people with Sickle Cell Disease could not get health insurance because sickle cell is a pre-existing condition, to the time when there was little money and no interest in research or professional training, to a time when patients and their families were fighting this fight alone?

For all of those with chronic disease, it’s as if we are living a very bad dream.

Time to wake up

For me, I want to wake up from that dream.  I want to look forward to a future where patients and families, where Joseph and Tiffany and Marissa and Ken and Marcus and all the others, will no longer have to worry about getting well-informed, professional treatment for their disease.

Where patients will no longer fear going to the Emergency Room

Where doctors and researchers have the funding they need to support them in their work toward the cure,

Where all children, those here in the United States along with those in Africa, India, and South America, will have access to treatments that can free them from pain and organ damage of sickle cell disease.

And where all people with this disease can be cured.

Translating great stem cell ideas into effective therapies

alzheimers

CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Stem cell agency funds clinical trials in three life-threatening conditions

strategy-wide

A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

A Patient Advocate’s Take on Sickle Cell Disease: The Pain and the Promise

September is National Sickle Cell Awareness Month. First officially recognized by the federal government in 1983, National Sickle Cell Awareness Month calls attention to sickle cell disease (SCD), a genetic disease that researchers estimate affects between 90,000 and 100,000 Americans. CIRM is funding a clinical trial focused on curing the disease with a stem cell-based gene therapy. 

People with this debilitating condition face a number of barriers in getting the help they need to keep their pain under control. In addition to the difficulty of accessing medication, they often have to overcome suspicion and discrimination.  Patient Advocate Nancy Rene, of Axis Advocacy  wrote the following blog about the problems families with SCD face.

Sickle Cell Disease Patient Advocates Adrienne Shapiro and Nancy Rene.

Sickle Cell Disease Patient Advocates Adrienne Shapiro and Nancy Rene.

Sickle Cell Disease: The Pain and the Promise

By Nancy M. Rene, co-founder, Axis Advocacy

The Disease

Sickle Cell Disease is a group of inherited red blood cell disorders. It is the most common genetic disease in the US. Close to 100,000 Americans have sickle cell disease.  Although it affects persons of African descent, it can also be found in Latino families and families from the Middle-East and India. World-wide there are at least 20 million people with the disease.

Normal red blood cells are round like doughnuts, and they move through small blood vessels in the body to deliver oxygen. Red blood cells in the person with sickle cell disease become hard, sticky and shaped like sickles. When these hard and pointed red cells go through the small blood vessels, they clog the flow and break apart. This causes pain, inflammation and organ damage.

The Pain and the Promise

In the last 30 years the United States has made great progress in treating sickle cell disease.  All states now have newborn screening and most children are living to adulthood. However, many children with SCD don’t receive important services to prevent serious complications from the disease.

Unfortunately, according the the American Society of Hematology, the mortality rate for adults appears to have increased during the same 30 years! Patients with SCD experience long delays in the ER, and are often accused of being drug seekers. Once admitted to the hospital they are confronted by medical staff with little understanding or empathy. Research from Dr. Michael DeBaun found that adults with this disease lack access to a primary care doctor who is knowledgeable about sickle cell.

The biggest Pain for those with sickle cell disease does not come from the disease itself but from treatment by the medical community.  When, for most people, going to the hospital represents a place to get help and relief from the burdens of a challenging disease, those with sickle cell see going to the hospital as going into battle. They “gear up” with copies of medical records and NIH guidelines, they make sure they have a diary to record inappropriate remarks from medical staff, they ask a friend to come along as an advocate to help them withstand the implied racism and institutional bias with which they are confronted. Even when new hospitals or clinics are built, they often do not live up to expectations, offering no emergency support or 24-hour access.

The promise of course comes from the diligent work of researchers and clinicians who run model programs.  Bone marrow transplants, while limited in use, have actually cured a number of young people, saving them from pain and organ damage that await their adult years. Pharmaceutical companies are completing clinical trials on several drugs that can reduce the symptoms of sickle cell at the molecular level. These drugs could greatly reduce the effects of the sickle cell crisis which often results in a lengthy hospital stay.

Stem cell research, while moving slowly, can be the holy grail of medical practice, curing many of the 100,000 Americans with sickle cell.  A cure would lead to avoiding the dreaded ER, being free of pain and organ damage, living a healthy life, and having children without worrying that they too would be born with this disease.

What is missing is linking research to clinical practice.  It is clear that the CDC, FDA and NIH have finally understood this missing piece.  The NIH published an extensive report, Guidelines for the The Treatment of Sickle Cell Disease, in 2014. NIH convened the 10th Annual Focus on Sickle Cell that brought researchers, clinicians, and other leaders together to make presentations on their work in sickle cell. The Sickle Cell Research Foundation convened an outstanding medical conference in Florida that again brought leaders together to gain knowledge from one another. ASH, the American Society of Hematology, is planning to launch a Sickle Cell Initiative this month.

We in the sickle cell community, patients, care-givers, and advocates, feel that we have finally got some big guns in this fight. Once doctors in all communities understand this disease, once they are aware of their own implicit bias and that of their institutions, there should be improvement in the treatment of people with this painful, debilitating illness.


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Stem cell stories that caught our eye: improving heart care, fixing sickle cell disease, stem cells & sugar

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

Using “disease in a dish” model to improve heart care
Medications we take to improve our quality of life might actually be putting our lives in danger. For example, some studies have shown that high doses of pain killers like ibuprofen can increase our risk of heart problems or stroke. Now a new study has found a way of using a person’s own cells, to make sure the drugs they are given help, and don’t hinder their recovery.

cardiacdisea

Cardiac muscle cells from boy with inherited heart arrhythmia.
Image: Emory University

Researchers at Emory University in Atlanta took skin cells from a teenage boy with an inherited heart arrhythmia, and turned them into induced pluripotent stem (iPS) cells – a kind of cell that can then be turned into any other cell in the body. They then turned the iPS cells into heart muscle cells and used those cells to test different medications to see which were most effective at treating the arrhythmia, without causing any toxic or dangerous side effects.

The study was published in Disease Models & Mechanisms. In a news release co-author Peter Fischbach, said the work enables them to study the impact on a heart cell, without taking any heart cells from patients:

“We were able to recapitulate in a petri dish what we had seen in the patient. The hope is that in the future, we will be able to do that in reverse order.”

Switching a gene “off” to ease sickle cell disease pain:
Sickle cell disease (SCD) is a nasty, inherited condition that not only leaves people in debilitating pain, but also shortens their lives. Now researchers at Dana-Farber and Boston Children’s Cancer and Blood Disorders Center have found a way that could help ease that pain in some patients.

SCD is caused by a mutation in hemoglobin, which helps carry oxygen around in our blood. The mutation causes normally soft, round blood cells to become stiff and sickle-shaped. These often stick together, blocking blood flow, causing intense pain, organ damage and even strokes.

In this study, published in the Journal of Clinical Investigation, researchers took advantage of the fact that SCD is milder in people whose red blood cells have a fetal form of hemoglobin, something which for most of us tails off after we are born. They found that by “switching off” a gene called BCL11A they could restart that fetal form of hemoglobin.

They did this in mice successfully. Senior author David Williams, in a story picked up by Health Medicine Network, says they now hope to try this in people:

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle-cell mutation. So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

CIRM already has a similar approach in clinical trials. UCLA’s Don Kohn is using a genetic editing technique to add a novel therapeutic hemoglobin gene that blocks sickling of the red blood cells and hopefully cure the patient altogether. This fun video gives a quick summary of the clinical trial:


How a stem cell’s sugar metabolism controls its transformation potential
While CIRM makes its push to fund 50 more stem cell-based clinical trials by 2020, we also continue to fund research that helps us better understand stem cells. Case in point, this week a UCLA research team funded in part by CIRM reported that an embryonic stem cell’s sugar metabolism changes as its develops and that this difference has big implications on cell fate.

glucose

Glucose

The study, published in Cell Stem Cell, compared so-called “naïve” and “primed” human embryonic stem cells (ESCs). The naïve cells represent a very early stage of embryo development and the primed cells represent a slightly later stage. All cells use the sugar, glucose, to provide energy, though the researchers discovered that the naive stem cells “ate up” glucose four times faster than the primed stem cells (A fascinating side note is they also found the exact opposite behavior in mice: naïve mouse ESCs metabolize glucose slower than primed mouse ESCs. This is a nice example of why it’s important to study human cells to understand human biology). It turns out this difference effects each cells ability to differentiate, or specialize, into a mature cell type. When the researchers added a drug that inhibits glucose metabolism to the naïve cells and stimulated them down a brain cell fate, three times more of the cells specialized into nerve cells.

Their next steps are to understand exactly how the change in glucose metabolism affects differentiation. As Heather Christofk mentioned in a university press release, these findings could ultimately help researchers who are manipulating stem cells to develop cell therapy products:

“Our study proves that if you carefully alter the sugar metabolism of pluripotent stem cells, you can affect their fate. This could be very useful for regenerative medicine.”

Here’s a new gene editing strategy to treat genetic blood disorders

If you’re taking a road trip across the country, you have a starting point and an ending point. How you go from point A to point B could be one of a million different routes, but the ultimate outcome is the same: reaching your final destination.

Yesterday scientists from St. Jude Children’s Research Hospital published exciting findings in the journal Nature Medicine on a new gene editing strategy that could offer a different route for treating genetic blood disorders such as sickle cell disease (SCD) and b-thalassemia.

The scientists used a gene editing tool called CRISPR. Unless you’ve been living under a rock, you’ve heard about CRISPR in the general media as the next, hot technology that could possibly help bring cures for serious diseases.

In simple terms, CRISPR acts as molecular scissors that facilitate cutting and pasting of DNA sequences at specific locations in the genome. For blood diseases like SCD and b-thalassemia, in which blood cells have abnormal hemoglobin, CRISPR gene editing offers ways to turn on and off genes that cause the clinical symptoms of these diseases.

Fetal vs. Adult hemoglobin

Before I get into the meat of this story, let’s take a moment to discuss hemoglobin. What is it? It’s a protein found in red blood cells that transports oxygen from the lungs to the rest of the body. Hemoglobin is made up of different subunits and the composition of these hemoglobin subunits change as newborns develop into adults.

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Healthy red blood cell (left), sickle cell (right).

Fetal hemoglobin (HbF) is comprised of a and g subunits while adult hemoglobin (HbA) is typically comprised of a and b subunits. Patients with SCD and b-thalassemia typically have mutations in the b globin gene. In SCD, this causes blood cells to take on an unhealthy, sickle cell shape that can clog vessels and eventually cause premature death. In b-thalassemia, the b-globin gene isn’t synthesized into protein at the proper levels and patients suffer from anemia (low red blood cell count).

One way that scientists are attempting to combat the negative side effects of mutant HbF is to tip the scales towards maintaining expression of the fetal g-globin gene. The idea spawned from individuals with hereditary persistence of fetal hemoglobin (HPFH), a condition where the hemoglobin composition fails to transition from HbF to HbA, leaving high levels of HbF in adult blood. Individuals who have HPFH and are predisposed to SCD or b-thalassemia amazingly don’t have clinical symptoms, suggesting that HbF plays either a protective or therapeutic role.

The current study is taking advantage of this knowledge in their attempt to treat blood disorders. Mitchell Weiss, senior author on the study and chair of the St. Jude Department of Hematology, explained the thought process behind their study:

“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits.”

CRISPRing blood stem cells for therapeutic purposes

Weiss and colleagues engineered red blood cells to have elevated levels of HbF in hopes of preventing symptoms of SCD. They used CRISPR to create a small deletion in a sequence of DNA, called a promoter, that controls expression of the hemoglobin g subunit 1 (HBG1) gene. The deletion elevates the levels of HbF in blood cells and closely mimics genetic mutations found in HPFH patients.

Weiss further explained the genome editing process in a news release:

Mitchell Weiss

Mitchell Weiss

“Our work has identified a potential DNA target for genome editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia. We have been able to snip that DNA target using CRISPR, remove a short segment in a “control section” of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”

The scientists genetically modified hematopoietic stem cells and blood progenitor cells from healthy individuals to make sure that their CRISPR gene editing technique was successful. After modifying the stem cells, they matured them into red blood cells in the lab and observed that the levels of HbF increased from 5% to 20%.

Encouraged by these results, they tested the therapeutic potential of their CRISPR strategy on hematopoietic stem cells from three SCD patients. While 25% of unmodified SCD blood stem cells developed red blood cells with a sickle cell shape under low-oxygen conditions (to induce stress), CRISPR edited SCD stem cells generated way fewer sickle cells (~4%) and had a higher level of HbF expression.

Many routes, one destination

The authors concluded that their genome editing technique is successful at switching hemoglobin expression from the adult form back to the fetal form. With further studies and safety testing, this strategy could be one day be developed into a treatment for patients with SCD and b-thalassemia

But the authors were also humble in their findings and admitted that there are many different genome editing strategies or routes for developing therapies for inherited blood diseases.

“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system.”

My personal opinion is the more strategies thrown into the pipeline the better. As things go in science, many of these strategies won’t be successful in reaching the final destination of curing one of these diseases, but with more shots on goal, our chances of developing a treatment that works there are a lot higher.


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Multi-Talented Stem Cells: The Many Ways to Use Them in the Clinic

CIRM kicked off the 2016 International Society for Stem Cell Research (ISSCR) Conference in San Francisco with a public stem cell event yesterday that brought scientists, patients, patient advocates and members of the general public together to discuss the many ways stem cells are being used in the clinic to develop treatments for patients with unmet medical needs.

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, an Investigator at the Gladstone Institutes and UCSF Professor, moderated the panel of four scientists and three patient advocates. He immediately captured the audience’s attention by showing a stunning video of human heart cells, beating in synchrony in a petri dish. Conklin explained that scientists now have the skills and technology to generate human stem cell models of cardiomyopathy (heart disease) and many other diseases in a dish.

Conklin went on to highlight four main ways that stem cells are contributing to human therapy. First is using stem cells to model diseases whose causes are still largely unknown (like with Parkinson’s disease). Second, genome editing of stem cells is a new technology that has the potential to offer cures to patients with genetic disorders like sickle cell anemia. Third, stem cells are known to secrete healing factors, and transplanting them into humans could be beneficial. Lastly, stem cells can be engineered to attack cancer cells and overcome cancer’s normal way of evading the immune system.

Before introducing the other panelists, Conklin made the final point that stem cell models are powerful because scientists can use them to screen and develop new drugs for diseases that have no treatments or cures. His lab is already working on identifying new drugs for heart disease using human induced pluripotent stem cells derived from patients with cardiomyopathy.

Scientists and Patient Advocates Speak Out

Malin Parmar, Lund University

Malin Parmar, Lund University

The first scientist to speak was Malin Parmar, a Professor at Lund University. She discussed the history of stem cell development for clinical trials in Parkinson’s disease (PD). Her team is launching the first in-human trial for Parkinson’s using cells derived from human pluripotent stem cells in 2016. After Parmar’s talk, John Lipp, a PD patient advocate. He explained that while he might look normal standing in front of the crowd, his PD symptoms vary wildly throughout the day and make it hard for him to live a normal life. He believes in the work that scientists like Parmar are doing and confidently said, “In my lifetime, we will find a stem cell cure for Parkinson’s disease.”

Adrienne Shapiro, Patient Advocate

Adrienne Shapiro, Patient Advocate

The next scientist to speak was UCLA Professor Donald Kohn. He discussed his lab’s latest efforts to develop stem cell treatments for different blood disorder diseases. His team is using gene therapy to modify blood stem cells in bone marrow to treat and cure babies with SCID, also known as “bubble-boy disease”. Kohn also mentioned their work in sickle cell disease (SCD) and in chronic granulomatous disease, both of which are now in CIRM-funded clinical trials. He was followed by Adrienne Shapiro, a patient advocate and mother of a child with SCD. Adrienne gave a passionate and moving speech about her family history of SCD and her battle to help find a cure for her daughter. She said “nobody plans to be a patient advocate. It is a calling born of necessity and pain. I just wanted my daughter to outlive me.”

Henry Klassen (UC Irvine)

Henry Klassen, UC Irvine

Henry Klassen, a professor at UC Irvine, next spoke about blinding eye diseases, specifically retinitis pigmentosa (RP). This disease damages the photo receptors in the back of the eye and eventually causes blindness. There is no cure for RP, but Klassen and his team are testing the safety of transplanting human retinal progenitor cells in to the eyes of RP patients in a CIRM-funded Phase 1/2 clinical trial.

Kristen MacDonald, RP patient

Kristen MacDonald, RP patient

RP patient, Kristen MacDonald, was the trial’s first patient to be treated. She bravely spoke about her experience with losing her vision. She didn’t realize she was going blind until she had a series of accidents that left her with two broken arms. She had to reinvent herself both physically and emotionally, but now has hope that she might see again after participating in this clinical trial. She said that after the transplant she can now finally see light in her bad eye and her hope is that in her lifetime she can say, “One day, people used to go blind.”

Lastly, Catriona Jamieson, a professor and Alpha Stem Cell Clinic director at UCSD, discussed how she is trying to develop new treatments for blood cancers by eradicating cancer stem cells. Her team is conducting a Phase 1 CIRM-funded clinical trial that’s testing the safety of an antibody drug called Cirmtuzumab in patients with chronic lymphocytic leukemia (CLL).

Scientists and Patients need to work together

Don Kohn, Catriona Jamieson, Malin Parmar

Don Kohn, Catriona Jamieson, Malin Parmar

At the end of the night, the scientists and patient advocates took the stage to answer questions from the audience. A patient advocate in the audience asked, “How can we help scientists develop treatments for patients more quickly?”

The scientists responded that stem cell research needs more funding and that agencies like CIRM are making this possible. However, we need to keep the momentum going and to do that both the physicians, scientists and patient advocates need to work together to advocate for more support. The patient advocates in the panel couldn’t have agreed more and voiced their enthusiasm for working together with scientists and clinicians to make their hopes for cures a reality.

The CIRM public event was a huge success and brought in more than 150 people, many of whom stayed after the event to ask the panelists more questions. It was a great kick off for the ISSCR conference, which starts today. For coverage, you can follow the Stem Cellar Blog for updates on interesting stem cell stories that catch our eye.

CIRM Public Stem Cell Event

CIRM Public Stem Cell Event

Sickle Cell Disease Leaves No Organ Untouched

“There really isn’t an organ in the body that isn’t affected by sickle cell disease.”

This striking comment was made by the Dr. Bertram Lubin, the CEO and President of the Children’s Hospital Oakland Research Institute (CHORI) and a CIRM Board Member.

Yesterday Dr. Lubin visited CIRM headquarters to talk about sickle cell disease (SCD). SCD is a group of inherited disorders caused by unhealthy, sickle-shaped red blood cells. People with SCD have abnormal hemoglobin, an important protein in red blood cells used to transport oxygen from the lungs to organs and tissues throughout the body.

The What, Why and Who of SCD

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

Genetic mutations in the hemoglobin genes lead to changes in the hemoglobin protein that cause normal, healthy disc-shaped red blood cells to take on a crescent, sickle shape. These sickle cells are a big problem because they stick to each other and to the walls of blood vessels, causing blockage and impeding blood flow. This leads to a plethora of clinical complications that we will touch on later in this blog.

Dr. Lubin shared some shocking facts including that 2 million African Americans are carriers of SCD mutations and 100,000 Americans have the disease. In the US, 1000 babies are born with SCD each year, but this number pales in comparison to the 1000 African babies that are born with SCD each day.

“So anything we do here with CIRM has a direct impact on sickle cell disease,” Lubin explained. “It’s something we should consider because it could have a global impact on SCD.”

SCD Affects Every Organ in the Body

Dr. Bertram Lubin

Dr. Bertram Lubin

Dr. Lubin next discussed a laundry list of clinical manifestations associated with SCD, making it clear that SCD is not just a blood disorder, it affects every organ and tissue in the body. Examples he gave included infection, enlarged spleen, stroke, bone disease, retinopathy, and gastro-intestinal complications. And these were only a handful of the symptoms he discussed that SCD patients deal with.

However, Dr. Lubin emphasized that early detection of SCD in babies can drastically improve the quality and length of life of SCD patients. He proudly explained how California was the first state to screen every newborn baby for SCD (a procedure that is now done in every state) and that CHORI’s Center for Sickle Cell Disease and Thalassemia is one of the major SCD programs in the world. Their center “strives to improve public awareness of these diseases, expand the current knowledge base, and ultimately, to provide innovative treatment, care – and cures.”

Dr. Lubin also commented on the importance of knowing if patients who go to the ER or doctor have SCD:

Dr. Bertram Lubin

Dr. Bertram Lubin

“With new born screening before we identified who had sickle cell disease, an African American child could come to the emergency room with a 103 F temperature. And they would say, well this is a virus, go home, and half of those kids would die by the next day. Because those with pneumococcal sepsis [a bacterial infection that SCD patients have an increased risk for] don’t last very long. Now when someone comes into the emergency room with a 103 F temperature and we know they have sickle cell, they get antibiotics right away. That told us there is a different way to do it and that really showed how genetics and public health can have an impact on the overall health of the population.”

Treatments and Hope for SCD

Dr. Lubin ended his talk by discussing the current management and treatment strategies for SCD patients. Early identification through universal newborn screening and family education are essential as well as preventative measures like penicillin and immunization to avoid infection.

As for therapeutic interventions, he mentioned blood transfusions, hydroxyurea treatments (which boosts the levels of healthy hemoglobin in blood cells), and bone marrow stem cell transplants. He said while bone marrow transplants have successfully treated some SCD patients, there are still many barriers to this form of treatment. Only 14% of families of SCD patients have an HLA-identical sibling donor and only 19% have an unrelated HLA-matched donor. Additionally, some doctors avoid recommending bone marrow transplants to SCD patients because of the risks for transplant rejection (graft vs. host disease) and death.

However, Dr. Lubin is hopeful that recent advances in stem cell research and genome engineering will one day make stem cell transplants the go-to treatment for SCD patients.

He ended with:

“The future of curative therapies that will have broad availability for SCD might follow advances in genomic correction of sickle mutation in hematopoietic [bone marrow] stem cells.”


Related Articles:

Stem cell stories that caught our eye: new CRISPR fix for sickle cell disease, saving saliva stem cells, jumping genes in iPSCs and lung stem cells.

An end run around sickle cell disease with CRISPR
The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)

Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.

So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.

But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:

“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”

Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.

Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth?
I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.

Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.

Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.

Keeping a Lid on Jumping Genes
Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.

While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.

To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.

Retrotransposons: curious pieces of DNA that can be transcribed into RNA, copied into DNA, and inserted to a new spot in your chromosomes.

The duplication and insertion of transposons into our chromosomes can be bad news for a cell

Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.

So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.

The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.

Great hope for lung stem cells
Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.

In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.

Related links

New Video: Defeating Sickle Cell Disease with Stem Cells + Gene Therapy

Suffering with an incurable illness is no laughing matter. But last year when we debuted the pilot episode of Stem Cells in Your Face, a lighthearted video series that describes specific diseases and explains the latest progress in stem cell-based therapies, we hoped that a mix of science and humor would help make the information stick in the minds of our viewers. We were thrilled, based on your comments, that you enjoyed watching Treating ALS with a Disease in a Dish as much as we enjoyed producing it and that you wanted to see more:

“Very informative yet easy to understand pilot episode! Hope to see more in this series soon!” “Might I suggest highlighting a different disease CIRM focuses on in each video?”

Ask and you shall receive. This week we’ve posted the second installment: Defeating Sickle Cell Disease with Stem Cells + Jean Gene Therapy which is being rolled out as a companion piece to our new blog feature series, Genes + Cells.

 The video highlights a CIRM-funded clinical trial at UCLA that is testing a stem cell and gene therapy treatment for sickle cell disease. This awful genetic disorder causes red blood cells to assume a sickle shape, clogging blood vessels and producing episodes of excruciating pain, called crises, and leading to progressive organ damage. By twenty years of age about 15 percent of people with sickle cell disease have had major strokes and by 40 almost half of the patients have significant mental dysfunction. The disease strikes one in 500 African Americans and 1 in 36,000 Hispanic people. A standard treatment for sickle cell disease is a blood transfusion but the benefits are short-lived and require repeated procedures. Bone marrow transplants can be curative but they require a well-matched blood donor which is hard to find and can still be very risky. The UCLA team, on the other hand, aims to correct the sickle cell genetic mutation within the blood stem cells of the patient, which in theory could provide a life-long supply of normal shaped red blood cells. Don Kohn, the lead scientist on the team, explains their strategy in the video:

“The approach that we’re looking at would be to take the patient’s own bone marrow, isolate the [blood] stem cells, in the laboratory put in the gene we’ve been working on that prevents the red blood cells from sickling. So transplanting their own bone marrow back to them in theory should be safe, we don’t have to worry about rejection.“

If all goes well, sickle cell disease may soon be a thing of the past. As patient advocate Adrienne Shapiro has so eloquently stated in a previous Stories of Hope blog post:

“It’s my true belief that I’m going to be the last woman in my family to have a child with sickle cell disease. My afflicted daughter is going to be the last child to suffer, and my other daughter [who does not have the disease but carries the sickle cell mutation] is going to be the last one to fear [passing on the disease to her children]. Stem cells are going to fix this for us and many other families.”

This clinical trial represents one of the first trials to be part of CIRM’s Alpha Stem Cell Network. To learn more, visit our Alpha Clinic webpage. And for more details about CIRM-funding of sickle cell disease research visit these pages: