CIRM & NHLBI Create Landmark Agreement on Curing Sickle Cell Disease

CIRM Board approves first program eligible for co-funding under the agreement

Adrienne Shapiro, co-founder of Axis Advocacy, with her daughter Marissa Cors, who has Sickle Cell Disease.

Sickle Cell disease (SCD) is a painful, life-threatening blood disorder that affects around 100,000 people, mostly African Americans, in the US. Even with optimal medical care, SCD shortens expected lifespan by decades.  It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells.  Under a variety of environmental conditions, stress or viral illness, these abnormal red blood cells cause severe anemia and blockage of blood vessels leading to painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

On April 29th the governing Board of the California Institute for Regenerative Medicine (CIRM) approved $4.49 million to Dr. Mark Walters at UCSF Benioff Children’s Hospital in Oakland to pursue a gene therapy cure for this devastating disease. The gene therapy approach uses CRISPR-Cas9 technology to correct the genetic mutation that leads to sickle cell disease. This program will be eligible for co-funding under the landmark agreement between CIRM and the National Heart, Lung and Blood Institute (NHLBI) of the NIH.

This CIRM-NHLBI agreement was finalized this month to co-fund cell and gene therapy programs under the NIH “Cure Sickle Cell” initiative.  The goal is to markedly accelerate the development of cell and gene therapies for SCD. It will deploy CIRM’s resources and expertise that has led to a portfolio of over 50 clinical trials in stem cell and regenerative medicine.     

“CIRM currently has 23 clinical stage programs in cell and gene therapy.  Given the advancements in these approaches for a variety of unmet medical needs, we are excited about the prospect of leveraging this to NIH-NHLBI’s Cure Sickle Cell Initiative,” says Maria T. Millan, M.D., the President and CEO of CIRM. “We are pleased the NHLBI sees value in CIRM’s acceleration and funding program and look forward to the partnership to accelerate cures for sickle cell disease.”

“There is a real need for a new approach to treating SCD and making life easier for people with SCD and their families,” says Adrienne Shapiro, the mother of a daughter with SCD and the co-founder of Axis Advocacy, a sickle cell advocacy and education organization. “Finding a cure for Sickle Cell would mean that people like my daughter would no longer have to live their life in short spurts, constantly having their hopes and dreams derailed by ER visits and hospital stays.  It would mean they get a chance to live a long life, a healthy life, a normal life.”

CIRM is currently funding two other clinical trials for SCD using different approaches.  One of these trials is being conducted at City of Hope and the other trial is being conducted at UCLA.

Stanford scientist uses CRISPR-Cas9 and stem cells to develop potential “bubble baby” therapy

Dr. Matthew Porteus, professor of pediatrics at Stanford University.
Photo courtesy of Stanford Medicine.

Our immune system is an important and essential part of everyday life. It is crucial for fighting off colds and, with the help of vaccinations, gives us immunity to potentially lethal diseases. Unfortunately, for some infants, this innate bodily defense mechanism is not present or is severely lacking in function.

This condition is known as severe combined immunodeficiency (SCID), commonly nicknamed “bubble baby” disease because of the sterile plastic bubble these infants used to be placed in to prevent exposure to bacteria, viruses, and fungi that can cause infection. There are several forms of SCID, one of which involves a single genetic mutation on the X chromosome and is known as SCID-X1

Many infants with SCID-X1 develop chronic diarrhea, a fungal infection called thrush, and skin rashes. Additionally, these infants grow slowly in comparison to other children. Without treatment, many infants with SCID-X1 do not live beyond infancy.

SCID-X1 occurs almost predominantly in males since they only carry one X chromosome, with at least 1 in 50,000 baby boys born with this condition. Since females carry two X chromosomes, one inherited from each parent, they are unlikely to inherit two X chromosomes with the mutation present since it would require the father to have SCID-X1.

What if there was a way to address this condition by correcting the single gene mutation? Dr. Matthew Porteus at Stanford University is leading a study that has developed an approach to treat SCID-X1 that utilizes this concept.

By using CRISPR-Cas9 technology, which we have discussed in detail in a previous blog post, it is possible to delete a problematic gene and insert a corrected gene. Dr. Porteus and his team are using CRISPR-Cas9 to edit blood stem cells, which give rise to immune cells, which are the foundation of the body’s defense mechanism. In a study published in Nature, Dr. Porteus and his team have demonstrated proof of concept of this approach in an animal model.

The Stanford team was able to take blood stem cells from six infants with SCID-X1 and corrected them with CRISPR-Cas9. These corrected stem cells were then introduced into mice modeled to have SCID-X1. It was found that these mice were not only able to make immune cells, but many of the edited stem cells maintained their ability to continuously create new blood cells.

In a press release, Dr. Mara Pavel-Dinu, a member of the research team, said:

“To our knowledge, it’s the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model.”

CIRM has previously awarded Dr. Porteus with a preclinical development award aimed at developing gene correction therapy for blood stem cells for SCID-X1. In addition to this, CIRM has funded two other projects conducted by Dr. Porteus related to CRISPR-Cas9. One of these projects used CRISPR-Cas 9 to develop a treatment for chronic sinusitis due to cystic fibrosis and the second project used the technology to develop an approach for treating sickle cell disease.

CIRM has also funded four clinical trials related to SCID. Two of these trials are related to SCID-X1, one being conducted at St. Jude Children’s Research Hospital and the other at Stanford University. The third trial is related to a different form of SCID known as ADA-SCID and is being conducted at UCLA in partnership with Orchard Therapeutics. Finally, the last of the four trials is related to an additional form of SCID known as ART-SCID and is being conducted at UCSF.

CRISPR-Cas9 101: an overview and the role it plays in developing therapies

Illustration courtesy of TED website

There has been a lot of conversation surrounding CRISPR-Cas9 in these recent months as well as many sensational news stories. Some of these stories highlight the promise this technology holds, while others emphasize a word of caution. But what exactly does this technology do and how does it work? Here is a breakdown that will help you better understand.

To start off, CRISPR is a naturally occurring process found in bacteria used as an immune system to defend against viruses. CRISPR simply put, are strands of DNA segments that contain repeating patterns. There are “scissor like” CRISPR proteins that have the ability to cut DNA segments. When a copy of a virus enters the bacteria, these “scissor like” proteins cut a segment of DNA from the virus and insert it into CRISPR. A copy of the viral DNA is made and another “attack” protein known as Cas9 attaches to it. By binding to the viral copy, Cas9 is able to sense that virus. When the same virus tries to enter the bacteria, Cas9 is able to seek and destroy it.

You can view a more detailed video explaining this concept below.

Many scientists analyzed this process in detail and it was eventually discovered that this CRISPR-Cas9 complex could be used to removed unwanted genes and insert a corrected copy, revolutionizing the way that we view the approach towards treating a wide variety of genetic diseases.

In fact, researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the University of Massachusetts Medical School have developed a strategy using this complex to treat two inherited, lethal blood disorders, sickle cell disease (SCD) and beta thalassemia. Both of these diseases involve a mutation that effects production of red blood cells, which are produced by blood stem cells. In beta-thalassemia, the mutation prevent red blood cells from being able to carry enough oxygen, leading to anemia. In SCD, the mutations cause red blood cells to take on a “sickle” shape which can block blood vessels.

By using CRISPR-Cas9 to insert a corrected copy of the gene into a patient’s own blood stem cells, this team demonstrated that functional red blood cells can then be produced. These results pay the way for other blood disorders as well.

In a press release , Dr. Daniel Bauer, an attending physician with Dana-Farber and a senior author on both of these studies stated that,

“Combining gene editing with an autologous stem-cell transplant could be a therapy for sickle-cell disease, beta-thalassemia and other blood disorders.”

In a separate study, scientists at University of Massachusetts Medical School have developed a strategy that could be used to treat genetic disorders associated with unintentional repeats or copies of small DNA segments. These problematic small segments of DNA are called microduplications and cause as many as 143 different diseases, including limb-girdle muscular dystrophy, Hermansky-Pudlak syndrome, and Tay-Sachs.

Because these are issues caused by repeats or copies of small DNA segments, the CRISPR-Cas9 complex can be used to remove microduplications without having to insert any additional genetic material.

Dr. Scot A. Wolfe, a co-investigator of this study, stated that,

“It’s like hitting the reset button. We don’t have to add any corrective genetic material, instead the cell stitches the DNA back together minus the duplication. It’s a shortcut for gene correction with potential therapeutic appeal.”

Although there has been a lot progress made with this technology, there are still concerns that need to be addressed. An article in Science mentions how two studies have shown that CRISPR can still make unintended changes to DNA, which can be potentially dangerous. In the article, Dr. Jin-Soo Kim, a CRISPR researcher at Seoul National University is quoted as saying,

“It is now important to determine which component is responsible for the collateral mutations and how to reduce or avoid them.”

Overall, CRISPR-Cas9 has revolutionized the approach of precision medicine. A wide variety of diseases are caused by small, unexpected segments of DNA. By applying this approach found in bacteria to humans, we have uncovered a way to correct these segments at the microscopic level. However, there is still much that needs to be learned and perfected before it can be utilized in patients.

Midwest universities are making important tools to advance stem cell research

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iPSCs are not just pretty, they’re also pretty remarkable

Two Midwest universities are making headlines for their contributions to stem cell research. Both are developing important tools to advance this field of study, but in two unique ways.

Scientists at the University of Michigan (UM), have compiled an impressive repository of disease-specific stem cell lines. Cell lines are crucial tools for scientists to study the mechanics of different diseases and allows them to do so without animal models. While animal models have important benefits, such as the ability to study a disease within the context of a living mammal, insights gained from such models can be difficult to translate to humans and many diseases do not even have good models to use.

The stem cell lines generated at the Reproductive Sciences Program at UM, are thanks to numerous individuals who donated extra embryos they did not use for in vitro fertilization (IVF). Researchers at UM then screened these embryos for abnormalities associated with different types of disease and generated some 36 different stem cell lines. These have been donated to the National Institute of Health’s (NIH) Human Embryonic Stem Cell Registry, and include cell lines for diseases such as cystic fibrosis, Huntington’s Disease and hemophilia.

Using one such cell line, Dr. Peter Todd at UM, found that the genetic abnormality associated with Fragile X Syndrome, a genetic mutation that results in developmental delays and learning disabilities, can be corrected by using a novel biological tool. Because Fragile X Syndrome does not have a good animal model, this stem cell line was critical for improving our understanding of this disease.

In the next state over, at the University of Wisconsin-Madison (UWM), researchers are doing similar work but using induced pluripotent stem cells (iPSCs) for their work.

The Human Stem Cell Gene Editing Service has proved to be an important resource in expediting research projects across campus. They use CRISPR-Cas9 technology (an efficient method to mutate or edit the DNA of any organism), to generate human stem cell lines that contain disease specific mutations. Researchers use these cell lines to determine how the mutation affects cells and/or how to correct the cellular abnormality the mutation causes. Unlike the work at UM, these stem cell lines are derived from iPSCs  which can be generated from easy to obtain human samples, such as skin cells.

The gene editing services at UWM have already proved to be so popular in their short existence that they are considering expanding to be able to accommodate off-campus requests. This highlights the extent to which both CRISPR technology and stem cell research are being used to answer important scientific questions to advance our understanding of disease.

CIRM also created an iPSC bank that researchers can use to study different diseases. The  Induced Pluripotent Stem Cell (iPSC) Repository is  the largest repository of its kind in the world and is used by researchers across the globe.

The iPSC Repository was created by CIRM to house a collection of stem cells from thousands of individuals, some healthy, but some with diseases such as heart, lung or liver disease, or disorders such as autism. The goal is for scientists to use these cells to better understand diseases and develop and test new therapies to combat them. This provides an unprecedented opportunity to study the cell types from patients that are affected in disease, but for which cells cannot otherwise be easily obtained in large quantities.

Researcher claims to have made first gene-edited baby. But did it really happen?

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Claude Vorilhorn, founder of Raelism; Photo: courtesy thoughtco.com

Remember the Raelians? Probably not. But way back in 2002 the group, some described them as a cult, claimed it had created the world’s first cloned baby. The news made headlines all around the world raising fears we were stepping into uncharted scientific territory. Several weeks later the scientist brought in by the Raelians to verify their claims called it an “elaborate hoax.”

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He Jiankui: Photo courtesy MIT Technology Review

Fast forward 16 years and a Chinese scientist named He Jiankui of Shenzhen claims he has created the first genetically modified humans. Again, it is generating headlines around the world and alarming people. In an interview with CNBC, Hank Greely, a bioethicist at Stanford, said if it happened it was “criminally reckless and I unequivocally condemn the experiment.”

The question now is did it happen, or is this just another “elaborate hoax”?

The concerns about this story are real. The scientist claims he used CRISPR to modify embryos during fertility treatments, resulting in the birth of twin girls.

CRISPR has been making headlines all of its own in the last few years as a fast, cheap and efficient way of editing genes. CIRM supports research using CRISPR for problems such as sickle cell disease. The difference being that our research works with adults so any changes in their genes are just for them. Those changes are not passed on to future generations.

The work making headlines around the world used CRISPR on embryos, meaning a child born from one of those embryos would pass those changes on to future generations. In effect, creating a new kind of human being.

This approach raises all sorts of serious issues – scientific, ethical and moral – not the least of which is that the technique could create unknown mutations down the road that would be passed on to future generations.  That’s why in the US the editing of embryos for pregnancy is banned.

But almost as soon as the news was announced there were questions raised about it. The research was not published anywhere. A hospital that the researchers named in their ethical approval documents is denying any involvement.

If it did happen, it could open a new, and potentially frightening chapter in science. In an interview on CNN, Julian Savulescu, director of the Oxford Uehiro Centre for Practical Ethics at the University of Oxford, called the use of CRISPR in this manner as “genetic Russian Roulette.”

“If true, this experiment is monstrous. Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life, including the development of cancer.”

And in an interview on the BBC, Prof Robert Winston, Professor of Science and Society at Imperial College London, said: “If this is a false report, it is scientific misconduct and deeply irresponsible. If true, it is still scientific misconduct.”

Our best hope right now is that this is just a repeat of the Raelians. Our worst fear, is that it’s not.

New partnership to make CIRM supported treatment for type 1 diabetes even better

 

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ViaCyte’s PEC-Direct device. Image courtesy of ViaCyte

ViaCyte, a regenerative medicine company long backed by CIRM, announced a partnership with CRISPR Therapeutics to increase the number of people with Type 1 Diabetes (T1D) who could benefit from their PEC-Direct therapeutic implant.

Last year, CIRM granted ViaCyte $20 million to facilitate development of PEC-Direct, a device that both transplants pancreatic progenitor stem cells (the immature version of  islet cells, the insulin-producing cells that are destroyed in TID), and allows those cells to connect to the patient’s bloodstream to help them function more like normal islet cells. This treatment, currently in clinical trials, was initially targeted towards high risk patients because of the need to treat them with immunosuppressive therapy, to ensure that the patient’s immune system does not attack the implanted cells.

ViaCyte’s partnership with CRISPR Therapeutics aims to eliminate the need for immunosuppressive therapy by engineering the transplanted stem cells to evade the immune system prior to implanting in the patient. CRISPR Therapeutics is already using this gene editing approach in CAR-T based cancer therapies and has developed an important knowledge base in “immune-evasive gene editing.” Paul Laikind Ph.D., CEO and President of ViaCyte explains the importance of this partnership in a news release:

“Creating an immune-evasive gene-edited version of our technology would enable us to address a larger patient population than we could with a product requiring immunosuppression. CRISPR Therapeutics is the ideal partner for this program given their leading gene editing technology and expertise and focus on immune-evasive editing.”

Samarth Kulkarni, Ph.D., and CEO of CRISPR Therapeutics adds:

“We believe the combination of regenerative medicine and gene editing has the potential to offer durable, curative therapies to patients in many different diseases, including common chronic disorders like insulin-requiring diabetes.”

The hope is that this new approach could make this treatment available to everyone with T1D. The benefits of such a treatment option would be considerable as TID affects around 1.25 million Americans, and can lead to severe health complications such as kidney damage and heart disease. The initial goals of this collaboration are to develop a stem cell line that successfully evades the immune system, followed by developing a product that can be used in patients.

 

Has Regenerative Medicine Come of Age?

Signals logo

For the past few years the Signals blog site –  which offers an insiders’ perspectives on the world of regenerative medicine and stem cell research – has hosted what it calls a “Blog Carnival”. This is an event where bloggers from across the stem cell field are invited to submit a piece based on a common theme. This year’s theme is “Has Regenerative Medicine Come of Age?” Here’s my take on that question:

Many cultures have different traditions to mark when a child comes of age. A bar mitzvah is a Jewish custom marking a boy reaching his 13th birthday when he is considered accountable for his own actions. Among Latinos in the US a quinceañera is the name given to the coming-of-age celebration on a girl’s 15th birthday.

Regenerative Medicine (RM) doesn’t have anything quite so simple or obvious, and yet the signs are strong that if RM hasn’t quite come of age, it’s not far off.

For example, look at our experience at the California Institute for Regenerative Medicine (CIRM). When we were created by the voters of California in 2004 the world of stem cell research was still at a relatively immature phase. In fact, CIRM was created just six years after scientists first discovered a way to derive stem cells from human embryos and develop those cells in the laboratory. No surprise then that in the first few years of our existence we devoted a lot of funding to building world class research facilities and investing in basic research, to gain a deeper understanding of stem cells, what they could do and how we could use them to develop therapies.

Fast forward 14 years and we now have funded 49 projects in clinical trials – everything from stroke and cancer to spinal cord injury and HIV/AIDS – and our early funding also helped another 11 projects get into clinical trials. Clearly the field has advanced dramatically.

In addition the FDA last year approved the first two CAR-T therapies – Kymriah and Yescarta – another indication that progress is being made at many levels.

But there is still a lot of work to do. Many of the trials we are funding at the Stem Cell Agency are either Phase 1 or 2 trials. We have only a few Phase 3 trials on our books, a pattern reflected in the wider RM field. For some projects the results are very encouraging – Dr. Gary Steinberg’s work at Stanford treating people recovering from a stroke is tremendously promising. For others, the results are disappointing. We have cancelled some projects because it was clear they were not going to meet their goals. That is to be expected. These clinical trials are experiments that are testing, often for the first time ever in people, a whole new way of treating disease. Failure comes with the territory.

As the number of projects moving out of the lab and into clinical trials increases so too are the other signs of progress in RM. We recently held a workshop bringing together researchers and regulators from all over the world to explore the biggest problems in manufacturing, including how you go from making a small batch of stem cells for a few patients in an early phase clinical trial to mass producing them for thousands, if not millions of patients. We are also working with the National Institutes of Health and other stakeholders in discussing the idea of reimbursement, figuring out who pays for these therapies so they are available to the patients who need them.

And as the field advances so too do the issues we have to deal with. The discovery of the gene-editing tool CRISPR has opened up all sorts of possible new ways of developing treatments for deadly diseases. But it has also opened up a Pandora’s box of ethical issues that the field as a whole is working hard to respond to.

These are clear signs of a maturing field. Five years ago, we dreamed of having these kinds of conversations. Now they are a regular feature of any RM conference.

The simple fact that we can pose a question asking if RM has come of age is a sign all by itself that we are on the way.

Like little kids sitting in the back of a car, anxious to get to their destination, we are asking “Are we there yet?” And as every parent in the front seat of their car responds, “Not yet. But soon.”

CRISPR Gene Editing Tool Linked to Unexpected Collateral DNA Damage

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Photo Credit: Genetic Literacy Project

 

CRISPR–Cas9 has been widely hailed as the gene editing tool of the future. But research, published in the journal Nature Biotechnology,  about the effects of CRISPR/Cas9, have found it can cause unexpected genetic damage which could lead to dangerous changes in some cells.

Scientists have also learned there may be some safety implications for gene therapies that are being developed using CRISPR/Cas9.

These results come on the heels of a few studies published last month which suggested the CRISPR gene editing tool may inadvertently increase cancer risk in some cells.

“We found that changes in the DNA have been seriously underestimated before now,” said Allan Bradley, a professor at Britain’s Wellcome Sanger Institute who co-led the research published on Monday.

CRISPR/Cas9 can alter sections of DNA in cells by cutting at specific points and introducing changes at that location and is seen by many as a promising way to create treatments for diseases such as HIV or cancer.

Bradley’s team carried out a full systematic study in both mouse and human cells and discovered that CRISPR/Cas9 frequently caused extensive mutations including large genetic rearrangements such as DNA deletions and insertions.

These could lead to important genes being switched on or off – as intended by the therapies – but could also have major unexpected implications, the scientists said.

While experts say treatments like these could inactivate a disease-causing gene, or correct a genetic mutation, much more research is still needed to ensure techniques are safe.