Gene editing

Investing in a stem cell treatment for Hurler syndrome

/ Katie Sharify / 1 Comment

The California Institute for Regenerative Medicine (CIRM) awarded $5,444,353 to Dr. Natalia Gomez-Ospina and her team at Stanford University for a late-stage preclinical program targeting Severe Mucopolysaccharidosis type 1, also known as Hurler syndrome. This is an inherited condition caused by a faulty gene.

Children with Hurler syndrome lack an enzyme that the body needs to digest sugar. As a result, undigested sugar molecules build up in the body, causing progressive damage to the brain, heart, and other organs.

There are no signs or symptoms of the condition at birth, although some have a soft out-pouching around the belly-button or lower abdomen. Those with severe MPS I generally begin to show other signs and symptoms of the disorder within the first year of life. There is no effective treatment and life expectancy for many of these children is only around ten years.

Dr. Gomez-Ospina will use the patient’s own blood stem cells that have been genetically edited to restore the missing enzyme. The goal of this preclinical program is to show the team can manufacture the needed cells, to complete safety studies and to apply to the US Food and Drug Administration for an Investigational New Drug (IND), the authorization needed to begin a clinical trial in people.

“The funding will pave the way for trials in people to realize a more effective therapy for this devastating disease,” Gomez-Ospina said. “We will also generate safety and toxicity data that could facilitate the application of our genome editing platform to other genetic disorders for which a significant unmet need still exists.”

Funding a Clinical Trial for a Functional Cure for HIV

/ Kevin McCormack / 2 Comments

The use of antiretroviral drugs has turned HIV/AIDS from a fatal disease to one that can, in many cases in the US, be controlled. But these drugs are not a cure. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) voted to approve investing $6.85 million in a therapy that aims to cure the disease.

This is the 82nd clinical trial funded by CIRM.

There are approximately 38 million people worldwide living with HIV/AIDS. And each year there are an estimated 1.5 million new cases. The vast majority of those living with HIV do not have access to the life-saving antiretroviral medications that can keep the virus under control. People who do have access to the medications face long-term complications from them including heart disease, bone, liver and kidney problems, and changes in metabolism.

The antiretroviral medications are effective at reducing the viral load in people with HIV, but they don’t eliminate it. That’s because the virus that causes AIDS can integrate its DNA into long-living cells in the body and remain dormant. When people stop taking their medications the virus is able to rekindle and spread throughout the body.

Dr. William Kennedy and the team at Excision Bio Therapeutics have developed a therapeutic candidate called EBT-101. This is the first clinical study using the CRISPR-based platform for genome editing and excision of the latent form of HIV-1, the most common form of the virus that causes AIDS in the US and Europe. The goal is to eliminate or sufficiently reduce the hidden reservoirs of virus in the body to the point where the individual is effectively cured.

“To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative,” says Dr. Maria Millan, President and CEO of CIRM. “In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.”

In a news release announcing they had dosed the first patient, Daniel Dornbusch, CEO of Excision, called it a landmark moment. “It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient and is expected to enable the first ever clinical assessment of a multiplexed, in vivo gene editing approach. We were able to reach this watershed moment thanks to years of innovative work by leading scientists and physicians, to whom we are immensely grateful. With this achievement, Excision has taken a major step forward in developing a one-time treatment that could transform the HIV pandemic by freeing affected people from life-long disease management and the stigma of disease.”

The Excision Bio Therapeutics team also scored high on their plan for Diversity, Equity and Inclusion. Reviewers praised them for adding on a partnering organization to provide commitments to serve underserved populations, and to engaging a community advisory board to help guide their patient recruitment.

CIRM has already invested almost $81 million in 20 projects targeting HIV/AIDS, including four clinical trials.

Tiny tools for the smallest of tasks, editing genes

/ Kevin McCormack / Leave a comment

YOU CAN LISTEN TO THIS BLOG AS AN AUDIOCAST ON SPOTIFY

Developing new tools to edit genes

Having the right tools to do a job is important. Try using a large screwdriver to tighten the screws on your glasses and you quickly appreciate that it’s not just the type of tool that’s important, it’s also the size. The same theory applies to gene editing. And now researchers at Stanford have developed a tool that can take on even the tiniest of jobs.

The tool involves the use of CRISPR. You may well have heard about CRISPR. The magazine New Scientist described it this way: “CRISPR is a technology that can be used to edit genes and, as such, will likely change the world.” For example, CIRM is funding research using CRISPR to help children born with severe combined immunodeficiency, a rare, fatal immune disorder.  

There’s just one problem. Right now, CRISPR is usually twinned with a protein called Cas9. Together they are used to remove unwanted genes and insert a corrected copy of the bad gene. However, that CRISPR-Cas9 combination is often too big to fit into all our cells. That may seem hard to understand for folks like me with a limited science background, but trust the scientists, they aren’t making this stuff up.

To address that problem, Dr. Stanley Qi and his team at Stanford created an even smaller version, one they call CasMINI, to enable them to go where Cas9 can’t go. In an article on Fierce Biotech, Dr. Qi said this mini version has some big benefits: “If people sometimes think of Cas9 as molecular scissors, here we created a Swiss knife containing multiple functions. It is not a big one, but a miniature one that is highly portable for easy use.”

How much smaller is the miniature version compared to the standard Cas9? About half the size, 529 amino acids, compared to Cas9’s 1,368 amino acids.”

The team conclude their study in the journal Molecular Cell saying this could have widespread implications for the field: “This provides a new method to engineer compact and efficient CRISPR-Cas effectors that can be useful for broad genome engineering applications, including gene regulation, gene editing, base editing, epigenome editing, and chromatin imaging.”

Progress in the fight against Sickle Cell Disease

/ Kevin McCormack / 1 Comment
Marissa Cors, sickle cell disease patient advocate

Last November Marissa Cors, a patient advocate in the fight against Sickle Cell Disease (SCD), told the Stem Cellar “A stem cell cure will end generations of guilt, suffering, pain and early death. It will give SCD families relief from the financial, emotional and spiritual burden of caring someone living with SCD. It will give all of us an opportunity to have a normal life. Go to school, go to work, live with confidence.” With each passing month it seems we are getting closer to that day.

CIRM is funding four clinical trials targeting SCD and another project we are supporting has just been given the green light by the Food and Drug Administration to start a clinical trial. Clearly progress is being made.

Yesterday we got a chance to see that progress. We held a Zoom event featuring Marissa Cors and other key figures in the fight against SCD, CIRM Science Officer Dr. Ingrid Caras and Evie Junior. Evie is a pioneer in this struggle, having lived with sickle cell all his life but now hoping to live his life free of the disease. He is five months past a treatment that holds out the hope of eradicating the distorted blood cells that cause such devastation to people with the disease.

You can listen to his story, and hear about the other progress being made. Here’s a recording of the Zoom event.

You can also join Marissa every week on her live event on Facebook, Sickle Cell Experience Live.

Stem Cell/Gene Therapy combo heals patients battling rare disorder

/ Kevin McCormack / Leave a comment
Brenden Whittaker and his dog: Photo by Colin McGuire

A few years ago, Brenden Whittaker was running out of time. Brenden was born with a rare condition called x-linked chronic granulomatous disease or XCGD. It meant he lacked a critical part of his immune system that protects against bacterial or fungal infections.

Over 22 years Brenden was in and out of the hospital hundreds of times. Twice he almost died. When antibiotics failed to clear up persistent infections surgeons had to remove parts of his lungs and liver.

Brenden felt he was running out of options. Then he signed up for a clinical trial (funded by CIRM) that would use his own stem cells to correct the problem. More than four years later Brenden is doing just fine.

And he’s not the only one. A new study, published in the journal Nature Medicine, shows that six other patients in the clinical trial are now in remission and have stopped taking any other medications.

Dr. Don Kohn: Photo courtesy UCLA

Don Kohn, the lead researcher on the team from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, says that in the past the only “cure” for people with CGD was a bone marrow transplant, but that was rarely an option for most patients. In a news release he said finding a perfect match for a transplant was difficult, and even then, patients had to take powerful anti-rejection medications to stop their body rejecting the transplant. So, they developed another approach, using genetically re-engineered stem cells from the patient themselves.

“With this gene therapy, you can use a patient’s own stem cells instead of donor cells for a transplant. This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection.”

The team removed blood stem cells from the patients and, in the lab, corrected the genetic mutation that caused CGD. They then returned those cells to the patients which, because they are stem cells, multiplied and created a new blood supply – one free of CGD – and repaired the immune system.

Brenden was the first of five patients treated in the US. Another four were treated in Europe. All were between the ages of 2 and 27 (CGD patients often die in their 20’s because of the impact of repeated infections).

  • Two patients died because of previously incurred infections
  • Six of the seven surviving patients have discontinued previous treatments
  • Four new patients have since been treated and are currently free of infections

Dr. Kohn said the results are really encouraging: “None of the patients had complications that you might normally see from donor cells and the results were as good as you’d get from a donor transplant — or better.”

The next step is for the researchers to work with the US Food and Drug Administration to get permission to carry out a larger trial, with the eventual goal of getting approval to make it available to all patients who need it.  

Regular readers of our blog will remember that Don Kohn also pioneered a similar approach in treating, and curing, children battling another rare immune disorder, severe combined immunodeficiency or SCID. You can read about that here.

As for Brenden, he is now in college and has his sights set on medical school. In 2016 we profiled him in our Annual Report and ran a long interview with him on the blog where he talked about the joys of mowing the lawn and learning to live without a deadly disease stalking him.

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

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Raelians

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.”

hejiankui

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.

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

/ Adonica Shaw / Leave a comment

 

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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/

 

 

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

/ Pallavi Penumetcha / 1 Comment

Hemophilia

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 Roundup: New understanding of Huntington’s; how stem cells can double your DNA; and using “the Gary Oldman of cell types” to reverse aging

/ Kevin McCormack / Leave a comment

This week’s roundup highlights how we are constantly finding out new and exciting ways that stem cells could help change the way we treat disease.

Our Cool Stem Cell Image of the Week comes from our first story, about unlocking some of the secrets of Huntington’s disease. It comes from the Laboratory of Stem Cell Biology and Molecular Embryology at The Rockefeller University

Huntington's neurons

A new approach to studying and developing therapies for Huntington’s disease

Researchers at Rockefeller University report new findings that may upend the way scientists study and ultimately develop therapies for Huntington’s disease, a devastating, inherited neurodegenerative disorder that has no cure. Though mouse models of the disease are well-established, the team wanted to focus on human biology since our brains are more complex than those of mice. So, they used CRISPR gene editing technology in human embryonic stem cells to introduce the genetic mutations that cause HD.

Though symptoms typically do not appear until adulthood, the researchers were surprised to find that in their human cell-based model of HD, abnormalities in nerve cells occur at the earliest steps in brain development. These results suggest that HD therapies should focus on treatments much earlier in life.

The researchers observed another unexpected twist: cells that lack Huntingtin, the gene responsible for HD, are very similar to cells found in HD. This suggests that too little Huntingtin may be causing the disease. Up until now, the prevailing idea has been that Huntington’s symptoms are caused by the toxicity of too much mutant Huntingtin activity.

We’ll certainly be keeping an eye on how further studies using this new model affect our understanding of and therapy development for HD.

This study was published in Development and was picked by Science Daily.

How you can double your DNA

dna

As you can imagine we get lots of questions about stem cell research here at CIRM. Last week we got an email asking if a stem cell transplant could alter your DNA? The answer is, under certain circumstances, yes it could.

A fascinating article in the Herald Review explains how this can happen. In a bone marrow transplant bad blood stem cells are killed and replaced with healthy ones from a donor. As those cells multiply, creating a new blood supply, they also carry the DNA for the donor.

But that’s not the only way that people may end up with dual DNA. And the really fascinating part of the article is how this can cause all sorts of legal and criminal problems.

One researcher’s efforts to reverse aging

gary-oldman

Gary Oldman: Photo courtesy Variety

“Stem cells are the Gary Oldman of cell types.” As a fan of Gary Oldman (terrific as Winston Churchill in the movie “Darkest Hour”) that one line made me want to read on in a profile of Stanford University researcher Vittorio Sebastiano.

Sebastiano’s goal is, to say the least, rather ambitious. He wants to reverse aging in people. He believes that if you can induce a person’s stem cells to revert to a younger state, without changing their function, you can effectively turn back the clock.

Sebastiano says if you want to achieve big things you have to think big:

“Yes, the ambition is huge, the potential applications could be dramatic, but that doesn’t mean that we are going to become immortal in some problematic way. After all, one way or the other, we have to die. We will just understand aging in a better way, and develop better drugs, and keep people happier and healthier for a few more years.”

The profile is in the journal Nautilus.

How a tiny patch of skin helped researchers save the life of a young boy battling a deadly disease

/ Kevin McCormack / 1 Comment

 

EB boy

After receiving his new skin, the boy plays on the grounds of the hospital in Bochum, Germany. Credit: RUB

By any standards epidermolysis bullosa (EB) is a nasty disease. It’s a genetic condition that causes the skin to blister, break and tear off. At best, it’s painful and disfiguring. At worst, it can be fatal. Now researchers in Italy have come up with an approach that could offer hope for people battling the condition.

EB is caused by genetic mutations that leave the top layer of skin unable to anchor to inner layers. People born with EB are often called “Butterfly Children” because, as the analogy goes, their skin is as fragile as the wings of a butterfly. There are no cures and the only treatment involves constantly dressing the skin, sometimes several times a day. With each change of dressing, layers of skin can be peeled away, causing pain.

epidermolysis-bullosa-29502

Hands of a person with EB

Life and death for one boy

For Hassan, a seven-year old boy admitted to the Burn Unit of the Children’s Hospital in Bochum, Germany, the condition was particularly severe. Since birth Hassan had repeatedly developed blisters all over his body, but several weeks before being admitted to the hospital his condition took an even more serious turn. He had lost skin on around 80 percent of his body and he was battling severe infections. His life hung in the balance.

Hassan’s form of EB was caused by a mutation in a single gene, called LAMB3. Fortunately, a team of researchers at the University of Modena and Reggio Emilia in Italy had been doing work in this area and had a potential treatment.

To repair the damage the researchers took a leaf out of the way severe burns are treated, using layers of skin to replace the damaged surface. In this case the team took a tiny piece of skin, about half an inch square, from Hassan and, in the laboratory, used a retrovirus to deliver a corrected version of the defective gene into the skin cells.

 

They then used the stem cells in the skin to grow sizable sheets of new skin, ranging in size from about 20 to 60 square inches, and used that to replace the damaged skin.

skin-gene-therapy-graphic-ap-ps-171108_3x5_992

In the study, published in the journal Nature, the researchers say the technique worked quickly:

“Upon removal of the non-adhering gauze (ten days after grafting) epidermal engraftment was evident. One month after grafting, epidermal regeneration was stable and complete. Thus approximately 80% of the patient’s TBSA (total body surface area) was restored by the transgenic epidermis.”

The engrafted skin not only covered all the damaged areas, it also proved remarkably durable. In the two years since the surgery the skin has remained, in the words of the researchers, “stable and robust, and does not blister, itch, or require ointment or medications.”

In an interview in Science, Jakub Tolar, an expert on EB at the University of Minnesota, talked about the significance of this study:

“It is very unusual that we would see a publication with a single case study anymore, but this one is a little different. This is one of these [studies] that can determine where the future of the field is going to go.”

Because the treatment focused on one particular genetic mutation it won’t be a cure for all EB patients, but it could provide vital information to help many people with the disease. The researchers identified a particular category of cells that seemed to play a key role in helping repair the skin. These cells, called holoclones, could be an important target for future research.

The researchers also said that if a child is diagnosed with EB at birth then skin cells can be taken and turned into a ready-made supply of the sheets that can be used to treat skin lesions when they develop. This would enable doctors to treat problems before they become serious, rather than have to try and repair the damage later.

As for Hassan, he is now back in school, leading a normal life and is even able to play soccer.