Stem Cell Agency invests in stem cell therapies targeting sickle cell disease and solid cancers

Today CIRM’s governing Board invested almost $10 million in stem cell research for sickle cell disease and patients with solid cancer tumors.

Clinical trial for sickle cell disease

City of Hope was awarded $5.74 million to launch a Phase 1 clinical trial testing a stem cell-based therapy for adult patients with severe sickle cell disease (SCD). SCD refers to a group of inherited blood disorders that cause red blood cells to take on an abnormal, sickle shape. Sickle cells clog blood vessels and block the normal flow of oxygen-carrying blood to the body’s tissues. Patients with SCD have a reduced life expectancy and experience various complications including anemia, stroke, organ damage, and bouts of excruciating pain.

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

CIRM’s President and CEO, Maria T. Millan, explained in the Agency’s news release:

Maria T. Millan

“The current standard of treatment for SCD is a bone marrow stem cell transplant from a genetically matched donor, usually a close family member. This treatment is typically reserved for children and requires high doses of toxic chemotherapy drugs to remove the patient’s diseased bone marrow. Unfortunately, most patients do not have a genetically matched donor and are unable to benefit from this treatment. The City of Hope trial aims to address this unmet medical need for adults with severe SCD.”

The proposed treatment involves transplanting blood-forming stem cells from a donor into a patient who has received a milder, less toxic chemotherapy treatment that removes some but not all of the patient’s diseased bone marrow stem cells. The donor stem cells are depleted of immune cells called T cells prior to transplantation. This approach allows the donor stem cells to engraft and create a healthy supply of non-diseased blood cells without causing an immune reaction in the patient.

Joseph Rosenthal, the Director of Pediatric Hematology and Oncology at the City of Hope and lead investigator on the trial, mentioned that CIRM funding made it possible for them to test this potential treatment in a clinical trial.

“The City of Hope transplant program in SCD is one of the largest in the nation. CIRM funding will allow us to conduct a Phase 1 trial in six adult patients with severe SCD. We believe this treatment will improve the quality of life of patients while also reducing the risk of graft-versus-host disease and transplant-related complications. Our hope is that this treatment can be eventually offered to SCD patients as a curative therapy.”

This is the second clinical trial for SCD that CIRM has funded – the first being a Phase 1 trial at UCLA treating SCD patients with their own genetically modified blood stem cells. CIRM is also currently funding research at Children’s Hospital of Oakland Research Institute and Stanford University involving the use of CRISPR gene editing technologies to develop novel stem cell therapies for SCD patients.

Advancing a cancer immunotherapy for solid tumors

The CIRM Board also awarded San Diego-based company Fate Therapeutics $4 million to further develop a stem cell-based therapy for patients with advanced solid tumors.

Fate is developing FT516, a Natural Killer (NK) cell cancer immunotherapy derived from an engineered human induced pluripotent stem cell (iPSC) line. NK cells are part of the immune system’s first-line response to infection and diseases like cancer. Fate is engineering human iPSCs to express a novel form of a protein receptor, called CD16, and is using these cells as a renewable source for generating NK cells. The company will use the engineered NK cells in combination with an anti-breast cancer drug called trastuzumab to augment the drug’s ability to kill breast cancer cells.

“CIRM sees the potential in Fate’s unique approach to developing cancer immunotherapies. Different cancers require different approaches that often involve a combination of treatments. Fate’s NK cell product is distinct from the T cell immunotherapies that CIRM also funds and will allow us to broaden the arsenal of immunotherapies for incurable and devastating cancers,” said Maria Millan.

Fate’s NK cell product will be manufactured in large batches made from a master human iPSC line. This strategy will allow them to treat a large patient population with a well characterized, uniform cell product.

The award Fate received is part of CIRM’s late stage preclinical funding program, which aims to fund the final stages of research required to file an Investigational New Drug (IND) application with the US Food and Drug Administration. If the company is granted an IND, it will be able to launch a clinical trial.

Scott Wolchko, President and CEO of Fate Therapeutics, shared his company’s goals for launching a clinical trial next year with the help of CIRM funding:

“Fate has more than a decade of experience in developing human iPSC-derived cell products. CIRM funding will enable us to complete our IND-enabling studies and the manufacturing of our clinical product. Our goal is to launch a clinical trial in 2019 using the City of Hope CIRM Alpha Stem Cell Clinic.”

Just a Mom: The Journey of a Sickle Cell Disease Patient Advocate [video]

Adrienne Shapiro will tell you that she’s just a mom.

And it’s true. She is just a mom. Just a mom who is the fourth generation of mothers in her family to have children born with sickle cell disease. Just a mom who was an early advocate of innovative stem cell and gene therapy research by UCLA scientist Dr. Don Kohn which has led to an on-going, CIRM-funded clinical trial for sickle cell disease. Just a mom who is the patient advocate representative on a Clinical Advisory Panel (CAP) that CIRM is creating to help guide this clinical trial.

She’s just a mom who has become a vocal stem cell activist, speaking to various groups about the importance of CIRM’s investments in both early stage research and clinical trials. She’s just a mom who was awarded a Stem Cell and Regenerative Medicine Action Award at last month’s World Stem Cell Summit. She’s just a mom who, in her own words, “sees a new world not just for her children but for so many other children”, through the promise of stem cell therapies.

Yep, she’s just a mom. And it’s the tireless advocacy of moms like Adrienne that will play a critical role in accelerating stem cell therapies to patients with unmet medical needs. We can use all the moms we can get.

Adrienne Shapiro speaks to the CIRM governing Board about her journey as a patient advocate

A new study suggests CRISPR gene editing therapies should be customized for each patient

You know a scientific advance is a big deal when it becomes the main premise and title of a Jennifer Lopez-produced TV drama. That’s the case for CRISPR, a revolutionary gene-editing technology that promises to yield treatments for a wide range of genetic diseases.

In fact, clinical trials using the CRISPR method are already underway with more on the horizon. And at CIRM, we’re funding several CRISPR projects including a candidate gene and stem cell therapy that applies CRISPR to repair a genetic mutation found in sickle cell anemia patients.

geneeditingclip2

Animation by Todd Dubnicoff/CIRM

While these projects are moving full steam ahead, a study published this week in PNAS suggests a note of caution. They report that the natural genetic variability that is found when comparing  the DNA sequences of individuals has the potential to negatively impact the effectiveness of a CRISPR-based treatment and in some cases, could lead to dangerous side effects. As a result, the research team – a collaboration between Boston Children’s Hospital and the University of Montreal – recommends that therapy products using CRISPR should be customized to take into account the genetic variation between patients.

CRISPR 101
While other gene-editing methods pre-date CRISPR, the gene-editing technique has taken the research community by storm because of its ease of use. Pretty much any lab can incorporate it into their studies. CRISPR protein can cut specific DNA sequence within a person’s cells with the help of an attached piece of RNA. It’s pretty straight-forward to customize this “guide” RNA molecule so that it recognizes a desired DNA sequence that is in need of repair or modification.

https://player.vimeo.com/video/112757040

Because CRISPR activity heavily relies on the guide RNA molecule’s binding to a specific DNA sequence, there have been on-going concerns that a patient’s genetic variability could hamper the effectiveness of a given CRISPR therapy if it didn’t bind well. Even worse, if the genetic variability caused the CRISPR product to bind and inactivate a different region of DNA, say a gene responsible for suppressing cancer growth, it could lead to dangerous, so-called off target effects.

Although, studies have been carried out to measure the frequency of these potential CRISPR mismatches, many of the analyses depend on a reference DNA sequence from one individual. But as senior author Stuart Orkin, of Dana-Farber Boston Children’s Cancer and Blood Disorders Center, points out in a press release, this is not an ideal way to gauge CRISPR effectiveness and safety:

orkin

Stuart Orkin

“Humans vary in their DNA sequences, and what is taken as the ‘normal’ DNA sequence for reference cannot account for all these differences.”

 

 

One DNA sequence is not like the other
So, in this study, the research team analyzed previously published DNA sequence data from 7,444 people. And they focused on 30 disease genes that various researchers were targeting with CRISPR gene-editing. The team also generated 3,000 different guide RNAs with which to target those 30 disease genes.

The analysis showed that, in fact, about 50 percent of the guide RNAs could potentially have mismatches due to genetic variability found in these patients’ DNA sequences. These mismatches could lead to less effective binding of CRISPR to the disease gene target, which would reduce the effectiveness of the gene editing. And, though rare, the team also found cases in which an individual’s genetic variability could cause the CRISPR guide RNA to bind and cut in the wrong spot.

Matthew Canver, an MD-PhD student at Harvard Medical School who is also an author in the study, points out these less-than-ideal activities could also impact other gene editing techniques. Canver gives an overall recommendation how to best move forward with CRISPR-based therapy development:

canver, matthew

Matthew Canver

“The unifying theme is that all these technologies rely on identifying stretches of DNA bases very specifically. As these gene-editing therapies continue to develop and start to approach the clinic, it’s important to make sure each therapy is going to be tailored to the patient that’s going to be treated.”

 

CIRM-Funded Clinical Trials Targeting Blood and Immune Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Today we are featuring trials in our blood and immune disorders portfolio, specifically focusing on sickle cell disease, HIV/AIDS, severe combined immunodeficiency (SCID, also known as bubble baby disease) and rare disease called chronic granulomatous disease (CGD).

CIRM has funded a total of eight trials targeting these disease areas, all of which are currently active. Check out the infographic below for a list of those trials.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

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.


Related Links:

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.

0a448-sicklecellimage

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.


Related links: