Join us tomorrow at noon for “Ask the Stem Cell Team about Sickle Cell Disease”, a FaceBook Live Event

As an early kick off to National Sickle Cell Awareness Month – which falls in September every year – CIRM is hosting a “Ask the Stem Cell Team” FaceBook Live event tomorrow, August 28th, from noon to 1pm (PDT).

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The live broadcast will feature two scientists and a patient advocate who are working hard to bring an end to sickle cell disease, a devastating, inherited blood disorder that largely targets the African-American community and to a lesser degree the Hispanic community.

You can join us by logging onto Facebook and going to this broadcast link: https://bit.ly/2o4aCAd

Also, make sure to “like” our FaceBook page before the event to receive a notification when we’ve gone live for this and future events. If you miss tomorrow’s broadcast, not to worry. We’ll be posting it on our Facebook video page, our website, and YouTube channel shortly afterwards.

We want to answer your most pressing questions, so please email them directly to us beforehand at info@cirm.ca.gov.

For a sneak preview here’s a short video featuring our patient advocate speaker, Adrienne Shapiro. And see below for more details about Ms. Shapiro and our two other guests.

Adrienne Shapiro [Video: Todd Dubnicoff/CIRM]

  • Dr. Donald B. KohnUCLA MIMG BSCRC Faculty 180118

    Donald Kohn, MD

    Don Kohn, M.D. is a professor in the departments of Pediatrics and Microbiology, Immunology and Molecular Genetics in UCLA’s Broad Stem Cell Research Center. Dr. Kohn has a CIRM Clinical Stage Research grant in support of his team’s Phase 1 clinical trial which is genetically modifying a patient’s own blood stem cells to produce a correct version of hemoglobin, the protein that is mutated in these patients, which causes abnormal sickle-like shaped red blood cells. These misshapen cells lead to dangerous blood clots, debilitating pain and even death. The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

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    Mark Walters, MD

    Mark Walters, M.D., is a pediatric hematologist/oncologist and is director of the Blood & Marrow Transplantation Program at UCSF Benioff Children’s Hospital Oakland. Dr. Walters has a CIRM-funded Therapeutic Translation Research grant which aims to improve Sickle Cell Disease (SCD) therapy by preparing for a clinical trial that might cure SCD after giving back sickle gene-corrected blood stem cells – using cutting-edge CRISPR gene editing technology – to a person with SCD. If successful, this would be a universal life-saving and cost-saving therapy.

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    Adrienne Shapiro

    Adrienne Shapiro is a patient advocate for SCD and the co-founder of the Axis Advocacy SCD patient education and support website. Shapiro is the fourth generation of mothers in her family to have children born with sickle cell disease.  She is vocal stem cell activist, speaking to various groups about the importance of CIRM’s investments in both early stage research and clinical trials. In January, she was awarded a Stem Cell and Regenerative Medicine Action Award at the 2018 World Stem Cell Summit.

Stem cell therapy offers a glimpse of hope for a student battling a deadly cancer

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Daniel Apodaca Image credit: CNN

“About a week later they gave me a call and mentioned the word ‘cancer’ to me. For a long time, I was depressed and then, I guess you accept it and try to make the most out of the time you have now.’

That is not something you expect to hear from a 24 year old. But for Daniel Apodaca that became, very suddenly, his reality. He was diagnosed with a rare, soft tissue cancer called epithelioid sarcoma. Fortunately for Daniel help was at hand, and a lot closer than he could ever have possibly anticipated.

Daniel is a student at UCLA. CIRM is funding a clinical trial run by UCLA’s Dr. Antoni Ribas that targets the same cancer Daniel is battling. The therapy re-programs a person’s own immune system to help fight the disease.

Daniel became patient #1 in that trial.

CNN reporter Rachel Crane profiled Dr. Ribas and the treatment he hopes will save Daniel’s life.

 

 

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.

For the first time, scientists entirely reprogram human skin cells to iPSCs using CRISPR

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CRISPR iPSC colony of human skin cells showing expression of SOX2 and TRA-1-60, markers of human embryonic pluripotent stem cells

Back in 2012, Shinya Yamanaka was awarded the Nobel Prize in Physiology or Medicine for his group’s identification of “Yamanaka Factors,” a group of genes that are capable of turning ordinary skin cells into induced pluripotentent stem cells (iPSCs) which have the ability to become any type of cell within the body. Discovery of iPSCs was, and has been, groundbreaking because it not only allows for unprecedented avenues to study human disease, but also has implications for using a patient’s own cells to treat a wide variety of diseases.

Recently, Timo Otonkoski’s group at the University of Helsinki along with Juha Kere’s group at the Karolinska Institutet and King’s College, London have found a way to program iPSCs from skin cells using CRISPR, a gene editing technology. Their approach allows for the induction, or turning on of iPSCs using the cells own DNA, instead of introducing the previously identified Yamanka Factors into cells of interest.

As detailed in their study, published in the journal Nature Communications, this is the first instance of mature human cells being completely reprogrammed into pluripotent cells using only CRISPR. Instead of using the canonical CRISPR system that allows the CAS9 protein (an enzyme that is able to cut DNA, thus rendering a gene of interest dysfunctional) to mutate any gene of interest, this group used a modified version of the CAS9 protein, which allows them to turn on or off the gene that CAS9 is targeted to.

The robustness of their approach lies in the researcher’s identification of a DNA sequence that is commonly found near genes involved in embryonic development. As CAS9 needs to be guided to genes of interest to do its job, identification of this common motif allows multiple genes associated with pluripotency to be activated in mature human skin cells, and greatly increased the efficiency and effectiveness of this approach.

In a press release, Dr. Otonkoski further highlights the novelty and viability of this approach:

“…Reprogramming based on activation of endogenous genes rather than overexpression of transgenes is…theoretically a more physiological way of controlling cell fate and may result in more normal cells…”

 

Gene-editing Technique in Mice Shows Promise for Genetic Disorder in Utero

 

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New research presents a promising new avenue for research into treating genetic conditions during fetal development.
Credit: © llhedgehogll / Fotolia

Each year roughly 16 million parents receive the heartbreaking news that their child is likely to be born with a severe genetic disorder or birth defect. And while these genetic conditions can often be detected during pregnancy, using amniocentesis, there haven’t been any treatment options to correct these genetic conditions before birth. Well – thanks to a group of researchers at Carnegie Mellon University and Yale University that could one day change and offer alternative treatment options for children with genetic disorders while they are still in the womb.

For the first time ever, according to a Carnegie Melon press release, scientists used a gene editing technique to successfully cure a genetic condition in a mouse in utero. Their findings, published in Nature Communications, not only present a promising new avenue for research into treating genetic conditions, but they also open the doors for additional treatment options in the future.

In this study, the researchers used a synthetic molecule called a peptide nucleic acid (PNA) as the basis for a gene editing technique. They had previously used this method to cure beta-thalassemia, a genetic blood disorder that results in the reduced production of hemoglobin, in adult mice. Their technique uses an FDA-approved nanoparticle to deliver PNA molecules, paired with donor DNA, to the site of a genetic mutation. When the PNA-DNA complex identifies a designated mutation, the PNA molecule binds to the DNA and unzips its two strands. The donor DNA then binds with the faulty DNA and spurs the cell’s DNA repair pathways into action, correcting the error.

The researchers believe that their technique might even be able to achieve higher success rates if they can administer it multiple times during gestation. They also hope to see if their technique can be applied to other conditions.

While this research is promising there is a long way to go before the team will be ready to test it in people. However, one CIRM-supported project has already reached that milestone. Dr. Tippi MacKenzie and her team at UCSF are using in utero blood stem cell transplants from the mother to the fetus to help treat alpha thalassemia major, a blood disorder that is almost always fatal.

We recently blogged about this research and how it helped one couple deliver a healthy baby.

https://blog.cirm.ca.gov/2018/06/04/cirm-funded-study-results-in-the-first-ever-in-utero-stem-cell-transplant-to-treat-alpha-thalassemia/

 

 

Video: Behind the scenes of a life-saving gene therapy stem cell treatment

“We were so desperate. When we heard about this treatment were willing to do anything to come here.”

In the above quote from Zahraa El Kerdi, “here” refers to UCLA, a world away from her hometown in Lebanon. In September 2015, Zahree gave birth to a son, Hussein, who appeared perfectly healthy. But by six months, he was barely clinging to life due to an inherited blood disorder, ADA-SCID, also called Bubble Baby disease. The disorder left Hussein without a functioning immune system so even a common cold could prove deadly. In fact, SCID babies rarely survive past one year of age. Up until now, no treatment options existed for the disease.

But Zahraa and her husband Ali heard about a CIRM-funded clinical trial, led by Donald Kohn, M.D. at UCLA, that could modify Hussein’s blood stem cells to fix the gene problem that’s causing his disease. The El Kerdi’s 7500-mile journey to save Hussein’s life is captured in a wonderful, five-minute video produced by UCLA’s Broad Stem Cell Research Center.

With before and after scenes of Hussein’s treatment as well as animation describing how the therapy works, the short documentary is equal parts heart wrenching, uplifting and educational. Basically, what I’m trying to say is, it’s a must-see and available to view above.

The story behind the book about the Stem Cell Agency

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Don Reed at his book launch: Photo by Todd Dubnicoff

WHY I WROTE “CALIFORNIA CURES”  By Don C. Reed

It was Wednesday, June 13th, 2018, the launch day for my new book, “CALIFORNIA CURES: How the California Stem Cell Research Program is Fighting Your Incurable Disease!”

As I stood in front of the audience of scientists, CIRM staff members, patient advocates, I thought to myself, “these are the kind of people who built the California stem cell program.” Wheelchair warriors Karen Miner and Susan Rotchy, sitting in the front row, typified the determination and resolve typical of those who fought to get the program off the ground. Now I was about to ask them to do it one more time.

My first book about CIRM was “STEM CELL BATTLES: Proposition 71 and Beyond. It told the story of  how we got started: the initial struggles—and a hopeful look into the future.

Imagine being in a boat on the open sea and there was a patch of green on the horizon. You could be reasonably certain those were the tops of coconut trees, and that there was an island attached—but all you could see was a patch of green.

Today we can see the island. We are not on shore yet, but it is real.

“CALIFORNIA CURES” shows what is real and achieved: the progress the scientists have made– and why we absolutely must continue.

For instance, in the third row were three little girls, their parents and grandparents.

One of them was Evangelina “Evie” Vaccaro, age 5. She was alive today because of CIRM, who had funded the research and the doctor who saved her.

Don Reed and Evie and Alysia

Don Reed, Alysia Vaccaro and daughter Evie: Photo by Yimy Villa

Evie was born with Severe Combined Immunodeficiency (SCID) commonly called the “bubble baby” disease. It meant she could never go outside because her immune system could not protect her.  Her mom and dad had to wear hospital masks to get near her, even just to give her a hug.

But Dr. Donald Kohn of UCLA operated on the tiny girl, taking out some of her bone marrow, repairing the genetic defect that caused SCID, then putting the bone marrow back.

Today, “Evie” glowed with health, and was cheerfully oblivious to the fuss she raised.

I was actually a little intimidated by her, this tiny girl who so embodied the hopes and dreams of millions. What a delight to hear her mother Alysia speak, explaining  how she helped Evie understand her situation:  she had “unicorn blood” which could help other little children feel better too.

This was CIRM in action, fighting to save lives and ease suffering.

If people really knew what is happening at CIRM, they would absolutely have to support it. That’s why I write, to get the message out in bite-size chunks.

You might know the federal statistics—133 million children, women and men with one or more chronic diseases—at a cost of $2.9 trillion dollars last year.

But not enough people know California’s battle to defeat those diseases.

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Adrienne Shapiro at the book launch: Photo by Todd Dubnicoff

Champion patient advocate Adrienne Shapiro was with us, sharing a little of the stress a parent feels if her child has sickle cell anemia, and the science which gives us hope:  the CIRM-funded doctor who cured Evie is working on sickle cell now.

Because of CIRM, newly paralyzed people now have a realistic chance to recover function: a stem cell therapy begun long ago (pride compels me to mention it was started by the Roman Reed Spinal Cord Injury Research Act, named after my son), is using stem cells to re-insulate damaged nerves in the spine.  Six people were recently given the stem cell treatment pioneered by Hans Keirstead, (currently running for Congress!)  and all six experienced some level of recovery, in a few cases regaining some use of their arms hands.

Are you old enough to remember the late Annette Funicello and Richard Pryor?  These great entertainers were stricken by multiple sclerosis, a slow paralysis.  A cure did not come in time for them. But the international cooperation between California’s Craig Wallace and Australia’s Claude Bernard may help others: by  re-insulating MS-damaged nerves like what was done with spinal cord injury.

My brother David shattered his leg in a motorcycle accident. He endured multiple operations, had steel rods and plates inserted into his leg. Tomorrow’s accident recovery may be easier.  At Cedars-Sinai, Drs. Dan Gazit and Hyun Bae are working to use stem cells to regrow the needed bone.

My wife suffers arthritis in her knees. Her pain is so great she tries to make only one trip a day down and up the stairs of our home.  The cushion of cartilage in her knees is worn out, so it is bone on bone—but what if that living cushion could be restored? Dr. Denis Evseenko of UCLA is attempting just that.

As I spoke, on the wall behind me was a picture of a beautiful woman, Rosie Barrero, who had been left blind by retinitis pigmentosa. Rosie lost her sight when her twin children were born—and regained it when they were teenagers—seeing them for the first time, thanks to Dr. Henry Klassen, another scientist funded by CIRM.

What about cancer? That miserable condition has killed several of my family, and I was recently diagnosed with prostate cancer myself. I had everything available– surgery, radiation, hormone shots which felt like harpoons—hopefully I am fine, but who knows for sure?

Irv Weissman, the friendly bear genius of Stanford, may have the answer to cancer.  He recognized there were cancer stem cells involved. Nobody believed him for a while, but it is now increasingly accepted that these cancer stem cells have a coating of protein which makes them invisible to the body’s defenses. The Weissman procedure may peel off that “cloak of invisibility” so the immune system can find and kill them all—and thereby cure their owner.

What will happen when CIRM’s funding runs out next year?

If we do nothing, the greatest source of stem cell research funding will be gone. We need to renew CIRM. Patients all around the world are depending on us.

The California stem cell program was begun and led by Robert N. “Bob” Klein. He not only led the campaign, was its chief writer and number one donor, but he was also the first Chair of the Board, serving without pay for the first six years. It was an incredible burden; he worked beyond exhaustion routinely.

Would he be willing to try it again, this time to renew the funding of a successful program? When I asked him, he said:

“If California polls support the continuing efforts of CIRM—then I am fully committed to a 2020 initiative to renew the California Institute for Regenerative Medicine (CIRM).”

Shakespeare said it best in his famous “to be or not to be” speech, asking if it is “nobler …to endure the slings and arrows of outrageous fortune, or to take arms against a sea of troubles—and by opposing, end them”.

Should we passively endure chronic disease and disability—or fight for cures?

California’s answer was the stem cell program CIRM—and continuing CIRM is the reason I wrote this book.

Don C. Reed is the author of “CALIFORNIA CURES: How the California Stem Cell Program is Fighting Your Incurable Disease!”, from World Scientific Publishing, Inc., publisher of the late Professor Stephen Hawking.

For more information, visit the author’s website: www.stemcellbattles.com

 

SCID kid scores big on TV

Evie at book signing

One of the stories I never tire of telling is about Evie Vaccaro. She’s the little girl who was born with a fatal immune condition called severe combined immunodeficiency or SCID. Children with this condition have no immune system, no protection against infections, and often die in the first two years of life. But thanks to a stem cell therapy Evie was cured.

Evie is now five years old. A happy, healthy and, as we discovered last week, a very energetic kid. That’s because Evie and her family came to CIRM to celebrate the launch of Don Reed’s new book, “California Cures! How the California Stem Cell Program is Fighting Your Incurable Disease”.

Don Reed and Evie and Alysia

Don Reed with Alysia and Evie Vaccaro – Photo courtesy Yimy Villa

Don’s book is terrific – well, it’s about CIRM so I might be biased – but Evie stole the show, and the hearts of everyone there.

KTVU, the local Fox News TV station, did a couple of stories about Evie. Here’s one of them.

We will have more on Don Reed’s book later this week.

Coming up with a stem cell FIX for a life-threatening blood disorder

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A promising new treatment option for hemophiliacs is in the works at the Salk Institute for Biological Sciences. Patients with Hemophilia B experience uncontrolled, and sometimes life threatening, bleeding due to loss or improper function of Factor IX (FIX), a protein involved in blood clotting. There is no cure for the disease and patients rely on routine infusions of FIX to prevent excessive blood loss. As you can imagine, this treatment regimen is both time consuming and expensive, while also becoming less effective over time.

Salk researchers, partially funded by CIRM, aimed to develop a more long-term solution for this devastating disease by using the body’s own cells to fix the problem.

In the study, published in the journal Cell Reports, They harvested blood cells from hemophiliacs and turned them into iPSCs (induced pluripotent stem cells), which are able to turn into any cell type. Using gene editing, they repaired the iPSCs so they could produce FIX and then turned the iPSCs into liver cells, the cell type that naturally produces FIX in healthy individuals.

One step therapy

To test whether these FIX-producing liver cells were able to reduce excess blood loss, the scientists injected the repaired human cells into a hemophiliac mouse. The results were very encouraging; they saw a greater than two-fold increase in clotting efficiency in the mice, reaching about a quarter of normal activity. This is particularly promising because other studies showed that increasing FIX activity to this level in hemophiliac humans significantly reduces bleeding rates. On top of that they also observed that these cells were able to survive and produce FIX for up to a year in the mice.

In a news release Suvasini Ramaswamy, the first author of the paper, said this method could eliminate the need for multiple treatments, as well as avoiding the immunosuppressive therapy that would be required for a whole liver transplant.

“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs. Rather than constant injections, you can do this in one shot.”

While these results provide an exciting new avenue in hemophilia treatment, there is still much more work that needs to be done before this type of treatment can be used in humans. This approach, however, is particularly exciting because it provides an important proof of principle that combining stem cell reprogramming with genetic engineering can lead to life-changing breakthroughs for treating genetic diseases that are not currently curable.

 

 

Stem Cell Agency’s supporting role in advancing research for rare diseases

Orchard

The recent agreement transferring GSK’s rare disease gene therapies to Orchard Therapeutics was good news for both companies and for the patients who are hoping this research could lead to new treatments, even cures, for some rare diseases. It was also good news for CIRM, which played a key role in helping Orchard grow to the point where this deal was possible.

In a news releaseMaria Millan, CIRM’s President & CEO, said:

“At CIRM, our value proposition is centered around our ability to advance the field of regenerative medicine in many different ways. Our funding and partnership has enabled the smooth transfer of Dr. Kohn’s technology from the academic to the industry setting while conducting this important pivotal clinical trial. With our help, Orchard was able to attract more outside investment and now it is able to grow its pipeline utilizing this platform gene therapy approach.”

Under the deal, GSK not only transfers its rare disease gene therapy portfolio to Orchard, it also becomes a shareholder in the company with a 19.9 percent equity stake. GSK is also eligible to receive royalties and commercial milestone payments. This agreement is both a recognition of Orchard’s expertise in this area, and the financial potential of developing treatments for rare conditions.

Dr. Millan says it’s further proof that the agency’s impact on the field of regenerative medicine extends far beyond the funding it offers companies like Orchard.

“Accelerating stem cell therapies to patients with unmet medical needs involves a lot more than just funding research; it involves supporting the research at every stage and creating partnerships to help it fulfill its potential. We invest when others are not ready to take a chance on a promising but early stage project. That early support not only helps the scientists get the data they need to show their work has potential, but it also takes some of the risk out of investments by venture capitalists or larger pharmaceutical companies.”

CIRM’s early support helped UCLA’s Don Kohn, MD, develop a stem cell therapy for severe combined immunodeficiency (SCID). This therapy is now Orchard’s lead program in ADA-SCID, OTL-101.

Sohel Talib, CIRM’s Associate Director Therapeutics and Industry Alliance, says this approach has transformed the lives of dozens of children born with this usually fatal immune disorder.

“This gene correction approach for severe combined immunodeficiency (SCID) has already transformed the lives of dozens of children treated in early trials and CIRM is pleased to be a partner on the confirmatory trial for this transformative treatment for patients born with this fatal immune disorder.”

Dr. Donald B. Kohn UCLA MIMG BSCRC Faculty 180118Dr. Kohn, now a member of Orchard’s scientific advisory board, said:

“CIRM funding has been essential to the overall success of my work, supporting me in navigating the complex regulatory steps of drug development, including interactions with FDA and toxicology studies that enhanced and helped drive the ADA-SCID clinical trial.”

CIRM funding has allowed Orchard Therapeutics to expand its technical operations footprint in California, which now includes facilities in Foster City and Menlo Park, bringing new jobs and generating taxes for the state and local community.

Mark Rothera, Orchard’s President and CEO, commented:

“The partnership with CIRM has been an important catalyst in the continued growth of Orchard Therapeutics as a leading company transforming the lives of patients with rare diseases through innovative gene therapies. The funding and advice from CIRM allowed Orchard to accelerate the development of OTL-101 and to build a manufacturing platform to support our development pipeline which includes 5 clinical and additional preclinical programs for potentially transformative gene therapies”.

Since CIRM was created by the voters of California the Agency has been able to use its support for research to leverage an additional $1.9 billion in funds for California. That money comes in the form of co-funding from companies to support their own projects, partnerships between outside investors or industry groups with CIRM-funded companies to help advance research, and additional funding that companies are able to attract to a project because of CIRM funding.