Stem cell gene therapy for Fabry disease shows positive results in patients

Darren Bidulka rests after his modified blood stem cells were transplanted into him at the Foothills Medical Centre in Calgary in 2017, allowing him to stop his enzyme therapy. (From left): Dr. Jeffrey Medin, Medical College of Wisconsin, Dr. Aneal Khan, the experimental trial lead in Calgary, and Darren Bidulka. Image Credit: Darren Bidulka

Fabry disease is an X-linked genetic disorder that can damage major organs and shorten lifespan. Without a functional version of a gene called GLA, our bodies are unable to make the correct version of an enzyme that breaks down a fat, and that in turn can lead to problems in the kidneys, heart and brain. It is estimated that one person in 40,000 to 60,000 has the disease and it affects men more severely than women since men only have one copy of the X chromosome. Current treatment consists of enzyme therapy infusions every two weeks but there is currently no cure for Fabry disease. 

However, a Canadian research team is conducting the world’s first pilot study to treat Fabry disease using a stem cell gene therapy approach. The researchers collected the patient’s own blood stem cells and used gene therapy to insert copies of the fully functional gene into the stem cells, allowing them to make the correct version of the enzyme. The newly modified stem cells were then transplanted back into each patient.

Five men participated in this trial and the results so far have been very encouraging. After treatment with the stem cell gene therapy, all patients began producing the corrected version of the enzyme to near normal levels within one week. With these initial results, all five patients were allowed to stop their biweekly enzyme therapy infusions. So far, only three patients decided to do so and are stable.

In a news release, Darren Bidulka, the first patient to be treated in the study, talked about how life changing this stem cell gene therapy has been for him.

“I’m really happy that this worked. What an amazing result in an utterly fascinating experience. I consider this a great success. I can lead a more normal life now without scheduling enzyme therapy every two weeks. This research is also incredibly important for many patients all over the world, who will benefit from these findings.”

CIRM is no stranger to stem cell gene therapy and its potential having funded clinical trials in various areas such as severe combined immunodeficiency (bubble baby disease), cystinosis, sickle cell disease, and various others. The broad range of genetic diseases it has been used in to treat patients further highlights its importance in scientific research.

The full results of this study were published in Nature Communications.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Scientists look at how the lung and brain respond differently to SARS-CoV-2 infection

UC San Diego School of Medicine researchers found approximately 10-fold higher SARS-CoV-2 infection (green) in lung organoids (left), compared to brain organoids (right). Image courtesy of UCSD Health

Since the start of the coronavirus pandemic early last year, scientists all over the world are still trying to better understand SARS-CoV-2, the virus that causes COVID-19. Although the more commonly known symptoms involve respiratory issues, there have been other long term problems observed in recovered patients. These consist of heart issues, fatigue, and neurological issues such as loss of taste and smell and “brain fog”.

To better understand this, Dr. Tariq Rana and a team of researchers at the UC San Diego School of Medicine are using stem cells to create lung and brain organoids to better understand how the virus interacts with the various organ systems and to better develop therapies that block infection. Organoids are 3D models made of cells that can be used to analyze certain features of the human organ being modeled. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. 

The team’s lung and brain organoids produced molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 is able to use these doorknobs to enter cells and establish infection.

Dr. Rana and his team then developed a pseudovirus, a noninfectious version of SARS-CoV-2, and attached a fluorescent label, allowing them to measure how effectively the virus binds in human lung and brain organoids as well as to evaluate the cells’ response. The team was surprised to see an approximately 10-fold higher SARS-CoV-2 infection in lung organoids compared to brain organoids. Additionally, treatment with TMPRSS2 inhibitors reduced infection levels in both organoids.

Besides differences in infection levels, the lung and brain organoids also differed in their responses to the virus. Infected lung organoids pumped out molecules intended to summon help from the immune system while infected brain organoids upped their production of molecules that plays a fundamental role in pathogen recognition and activation of the body’s own immune defenses.

In a news release from UC San Diego Health, Dr. Rana elaborates on the results of his study.

“We’re finding that SARS-CoV-2 doesn’t infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes.”

The next steps for Rana and his team is to develop SARS-CoV-2 inhibitors and test out how well they work in organoid models derived from people of a variety of racial and ethnic backgrounds that represent California’s diverse population. To carry out this research, CIRM awarded Dr. Rana a grant of $250,000, which is part of the $5 million in emergency funding for COVID-19 research that CIRM authorized at the beginning of the pandemic.

The full results of this study can be found in Stem Cell Reports.

Charting a course for the future

A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.

Unlocking a key behind why our bones get weaker as we age

Magnified image of a bone with osteoporosis. Photo Courtesy Sciencephoto.com

Getting older brings with it a mixed bag of items. If you are lucky you can get wiser. If you are not so lucky you can get osteoporosis. But while scientists don’t know how to make you wiser, they have gained some new insights into what makes bones weak and so they might be able to help with the osteoporosis.

Around 200 million people worldwide suffer from osteoporosis, a disease that causes bones to become so brittle that in extreme cases even coughing can lead to a fracture.

Scientists have known for some time that the cells that form the building blocks of our skeletons are found in the bone marrow. They are called mesenchymal stem cells (MSCs) and they have the ability to turn into a number of different kinds of cells, including bone or fat. The keys to deciding which direction the MSCs take are things called epigenetic factors, these basically control which genes are switched on or off and in what order. Now researchers from the UCLA School of Dentistry have identified an enzyme that plays a critical role in that process.

The team found that when the enzyme KDM4B is missing in MSCs those cells are more likely to become fat cells rather than bone cells. Over time that leads to weaker bones and more fractures.

In a news release Dr. Cun-Yu Wang, the lead researcher, said: “We know that bone loss comes with age, but the mechanisms behind extreme cases such as osteoporosis have, up until recently, been very vague.”

To see if they were on the right track the team created a mouse model that lacked KDM4B. Just as they predicted the MSCs in the mouse created more fat than bone, leading to weaker skeletons.

They also looked at mice who were placed on a high fat diet – something known to increase bone loss and weaker bones in people – and found that the diet seemed to reduce KDM4B which in turn produced weaker bones.

In the news release Dr. Paul Krebsbach, Dean of the UCLA School of Dentistry, said the implications for the research are enormous. “The work of Dr. Wang, his lab members and collaborators provides new molecular insight into the changes associated with skeletal aging. These findings are an important step towards what may lead to more effective treatment for the millions of people who suffer from bone loss and osteoporosis.”

The study is published in the journal Cell Stem Cell.

Tipping our hat to the good guys (& gals)

A search on Google using the term “stem cell blogs” quickly produces a host of sites offering treatments for everything from ankle, hip and knee problems, to Parkinson’s disease and asthma. Amazingly the therapies for those very different conditions all use the same kind of cells produced in the same way. It’s like magic. Sadly, it’s magic that is less hocus pocus and more bogus bogus.

The good news is there are blogs out there (besides us, of course) that do offer good, accurate, reliable information about stem cells. The people behind them are not in this to make a quick buck selling snake oil. They are in this to educate, inform, engage and enlighten people about what stem cells can, and cannot do.

So, here’s some of our favorites.

The Niche

This blog has just undergone a face lift and is now as colorful and easy to read as it is informative. It bills itself as the longest running stem cell blog around. It’s run by UC Davis stem cell biologist Dr. Paul Knoepfler – full disclosure, we have funded some of Paul’s work – and it’s a constant source of amazement to me how Paul manages to run a busy research lab and post regular updates on his blog.

The power of The Niche is that it’s easy for non-science folk – like me – to read and understand without having to do a deep dive into Google search or Wikipedia. It’s well written, informative and often very witty. If you are looking for a good website to check whether some news about stem cells is real or suspect, this is a great place to start.

Stem Cell Battles

This site is run by another old friend of CIRM’s, Don Reed. Don has written extensively about stem cell research in general, and CIRM in particular. His motivation to do this work is clear. Don says he’s not a doctor or scientist, he’s something much simpler:

“No. I am just a father fighting for his paralyzed son, and the only way to fix him is to advance cures for everyone. Also, my mother died of breast cancer, my sister from leukemia, and I myself am a prostate cancer survivor. So, I have some very personal reasons to support the California Institute for Regenerative Medicine and to want state funding for stem cell and other regenerative medicine research to continue in California!”

The power of Don’s writing is that he always tells human stories, real tales about real people. He makes everything he does accessible, memorable and often very funny. If I’m looking for ways to explain something complex and translate it into everyday English, I’ll often look at Don’s work, he knows how to talk to people about the science without having their eyes cloud over.

A Closer Look at Stem Cells

This is published by the International Society for Stem Cell Research (ISSCR), the leading professional organization for stem cell scientists. You might expect a blog from such a science-focused organization to be heavy going for the ordinary person, but you’d be wrong.

A Closer Look at Stem Cells is specifically designed for people who want to learn more about stem cells but don’t have the time to get a PhD. They have sections explaining what stem cells are, what they can and can’t do, even a glossary explaining different terms used in the field (I used to think the Islets of Langerhans were small islands off the coast of Germany till I went to this site).

One of the best, and most important, parts of the site is the section on clinical trials, helping people understand what’s involved in these trials and the kinds of things you need to consider before signing up for one.

Signals

Of course, the US doesn’t have a monopoly on stem cell research and that’s reflected in the next two choices. One is the Signals Blog from our friends to the north in Canada. This is an easy-to-read site that describes itself as the “Insiders perspective on the world of stem cells and regenerative medicine.” The ‘Categories ‘dropdown menu allows you to choose what you want to read, and it gives you lots of options from the latest news to a special section for patients, even a section on ethical and legal issues. 

EuroStemCell

As you may have guessed from the title this is by our chums across the pond in Europe. They lay out their mission on page one saying they want to help people make sense of stem cells:

“As a network of scientists and academics, we provide independent, expert-reviewed information and road-tested educational resources on stem cells and their impact on society. We also work with people affected by conditions, educators, regulators, media, healthcare professionals and policymakers to foster engagement and develop material that meets their needs.”

True to their word they have great information on the latest research, broken down by different types of disease, different types of stem cell etc. And like CIRM they also have some great educational resources for teachers to use in the classroom.

U.C. San Diego Scientist Larry Goldstein Joins Stem Cell Agency’s Board

Larry Goldstein, PhD.

Larry Goldstein PhD, has many titles, one of which sums up his career perfectly, “Distinguished Professor”. Dr. Goldstein has distinguished himself on many fronts, making him an ideal addition to the governing Board of the California Institute for Regenerative Medicine (CIRM).

Dr. Goldstein – everyone calls him Larry – is a Cell Biologist, Geneticist and Neuroscientist. He worked with many colleagues to launch the UC San Diego Stem Cell program, the Sanford Consortium for Regenerative Medicine and the Sanford Stem Cell Clinical Center. He has received the Public Service Award from the American Society for Cell Biology and has had a Public Policy Fellowship named for him by the International Society for Stem Cell Research. He is a member of the American Academy of Arts and Sciences and last year was named a member of the prestigious National Academy of Sciences.

“I look forward to working with the ICOC and CIRM staff to ensure that the best and most promising stem cell research and medicine is fostered and funded,” Larry said.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

He was appointed to the CIRM Board by Pradeep Khosla, the Chancellor of U.C. San Diego saying he is “gratified you are assuming this important role.”

Jonathan Thomas, JD, PhD., Chair of the CIRM Board, welcome the appointment saying “I have known Larry for many years and have nothing but the highest regard for him as a scientist, a leader, and a great champion of stem cell research. He is also an innovative thinker and that will be invaluable to us as we move into a second chapter in the life of CIRM.”

Larry was born in Buffalo, New York and grew up in Thousand Oaks, California. He graduated from UC San Diego with a degree in Biology in 1976 and from the University of Washington with a Ph. D. in Genetics in 1980. He joined the faculty in Cell and Developmental Biology at Harvard University in 1984 where he was promoted to Full Professor with tenure in 1990. He returned to UC San Diego and the Howard Hughes Medical Institute in 1993. After 45 years pursuing cutting edge lab-based research Larry is now transitioning to an administrative and executive role at UC San Diego where he will serve as the Senior Advisor for Stem Cell Research and Policy to the Vice Chancellor of Health Sciences.

He replaces David Brenner who is standing down after completing two terms on the Board.

Scientists use stem cells to create Neanderthal-like “mini-brain”

Alysson R. Muotri, Ph.D.

The evolution of modern day humans has always been a topic that has been shrouded in mystery. Some of what is known is that Neanderthals, an archaic human species that lived on this planet up until about 11,700 years ago, interbred with our species (Homo sapiens) at some point in time. Although their brains were about as big as ours, anthropologists think they must have worked differently due to the fact that they never achieved the sophisticated technology and artistry modern humans have.

Since brains do not fossilize, it has been challenging to see how these two early human species have changed over time. To help answer this question, Dr. Alysson Muotri and his team at UC San Diego created so-called “mini-brains” using stem cells and gene editing technology to better understand how the Neanderthal brain might have functioned.

For this study, Dr. Muotri and his team closely evaluated the differences in genes between modern day humans and Neanderthals. They found a total of 61 different genes, but for this study focused on one in particular that plays a role in influencing early brain development.

Brain organoids that carry a Neanderthal gene.
Image courtesy of the Muotri Lab and UCSD

Using gene editing technology, the team introduced the Neanderthal version of the gene into human stem cells. These stem cells, which have the ability to become various cell types, were then used to create brain cells. These cells eventually formed brain organoids or “mini-brains”, 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. In a previous CIRM funded study, Dr. Muotri had used “mini-brains” to model an autism spectrum disorder and help test treatments.

Dr. Muotri and his team found that the Neanderthal-like brain organoids looked very different than modern human brain organoids, having a distinctly different shape. Upon further analysis, the team found that modern and Neanderthal-like brain organoids also differed in the way their cells grow. Additionally, the way in which connections between neurons formed as well as the proteins involved in forming these connections differed between the two organoids. Finally, electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-like brain organoids.

According to Muotri, the neural network changes in Neanderthal-like brain organoids mimic the way newborn primates acquire new abilities more rapidly than human newborns.

In a news release from UCSD, Dr. Muotri discusses the next steps in advancing this research.

“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered. We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics.”

The full results of this study were published in Science.

UCSF Nursing Professor Joins CIRM Board

Elena Flowers, PhD, RN, newest member of the CIRM Board: Photo courtesy UCSF

Elena Flowers, PhD, RN, an associate professor of physiological nursing at the University of California, San Francisco (UCSF) is joining the Board of the California Institute for Regenerative Medicine (CIRM), the state’s Stem Cell Agency.

Dr. Flowers was appointed to the Board by State Controller Betty T. Yee who said: “Ms. Flowers’ experience and express commitment to equitable health outcomes for California’s diverse communities will bring a valued perspective to the work ahead.”

Dr. Flowers is a member of the UCSF Institute for Human Genetics and the International Society of Nurses in Genetics. As a researcher her work focuses on genomics involving precision medicine and risk factors for cardiovascular health and type 2 diabetes. She is also a teacher and has lectured internationally on issues such as topics from racial disparities in Type 2 Diabetes to the implications of genomic technologies for the nursing workforce.

CIRM Board Chair, Jonathan Thomas, PhD, JD, welcomed the appointment: “Dr. Flowers brings a wealth of experience and expertise to our Board and, as a nurse, she will bring a different perspective to the work we do and help us in trying to better address the needs of underserved communities.” 

“I am honored to have the opportunity to serve the citizens of California in this capacity,” says Dr. Flowers. “CIRM has ambitious goals, seeking to improve upon common limitations of public research agencies by its commitment to delivering meaningful findings and ultimately treatments for patients as rapidly as possible. I’m particularly committed to improving inclusion and access to these treatments across the entire diverse California population.”

Dr. Flowers got her undergraduate degree at UC Davis and then served as a research assistant at Zuckerberg San Francisco General Hospital. She then went on to get her MS and Doctor of Philosophy degrees at the UCSF School of Nursing.

In her spare time she has no spare time because she is the mother of two young daughters.

Biotechnology companies join forces in developing treatment for X-SCID

Jasper Therapeutics, Inc., a biotechnology company focused on blood stem cell therapies, and Graphite Bio, Inc., a biotechnology company focused on gene editing therapies to treat or cure serious diseases, announced a research and clinical collaboration for a treatment for X-SCID.

X-SCID, which stands for X-linked severe combined immunodeficiency, is a genetic disorder that interferes with the normal development of the immune system, leaving infants vulnerable to infections that most people can easily fight off. One treatment for X-SCID involves a blood stem cell transplant, in which the patient’s defective stem cells are wiped out with chemotherapy or radiation to make room for normal blood stem cells to take their place. Unfortunately, the problem with chemotherapy or radiation in young infants is that it can lead to lifelong effects such as neurological impairment, growth delays, infertility, and risk of cancer.

Fortunately, Jasper Therapeutics has developed JSP191, a non-toxic alternative to chemotherapy and radiation. It is an antibody that works by targeting and removing the defective blood forming stem cells. The approach has previously been used in a CIRM-funded clinical trial ($20M award) for X-SCID.

Graphite Bio has developed GPH201, the first-in-human investigational blood stem cell treatment that will be evaluated as a potential cure for patients suffering from X-SCID. GPH201 is generated using precise and efficient gene editing technology, It works by directly replacing a defective gene that causes problems with the immune system. The hope is that GPH201 will ultimately lead to the production of fully functional, healthy immune cells.

The ultimate goal of this collaboration is to use JSP191 as the non-toxic alternative to chemotherapy in patients in order to remove their defective blood stem cells. After that, the gene editing blood stem cell technology developed by Graphite Bio can be introduced to patients in order to treat X-SCID. The two companies have agreed to collaborate on research, and potentially a clinical study, evaluating JSP191 as the non-toxic conditioning agent for GPH201.

In a press release, Josh Lehrer, M.Phil., M.D., chief executive officer at Graphite Bio, expressed excitement about the collaboration between the two companies.

“This collaboration with Jasper demonstrates our shared commitment to pioneering novel therapeutic approaches with the potential to significantly improve the treatment experiences of individuals with devastating conditions who stand to benefit from gene replacement therapies, initially for patients with XSCID. GPH201 harnesses our targeted gene integration platform to precisely target the defective gene that causes XSCID and replace it with a normal copy.”

In the same press release, Bill Lis, executive chairman and CEO of Jasper Therapeutics, also expressed optimism in regards to the two companies teaming up.

“Our collaboration with Graphite Bio is an exciting opportunity to further advance the field of curative gene correction by combining a targeted gene integration platform with our first-in-class targeted CD117 antibody, JSP191, that has already demonstrated preliminary clinical efficacy and safety as a conditioning agent in X-SCID patients and those with blood cancers undergoing allogeneic hematopoietic stem cell transplant.”

Graphite Bio is also developing gene editing technology to help treat sickle cell disease.  It is currently supported by a CIRM  late stage preclinical grant ($4.8M award). Th goal is to complete the final preclinical studies, which will allow Graphite Bio to start clinical studies of the sickle cell disease gene therapy in sickle cell patients in 2021.