Each year, around 24,000 women in the US lose a pregnancy. One reason for this unfortunate occurrence are metabolic disorders, one of which is known as Sly syndrome and is caused by a single genetic mutation. In Sly syndrome, the body’s cells lack an enzyme necessary for proper cell function. Many fetuses with this condition die before birth but those that survive are treated with regular injections of the lacking enzyme. Unfortunately, patients can eventually develop an immune response to these injections and it cannot enter the brain after birth.
However, a team of researchers at UCSF are looking at exploring a potential treatment that could be delivered in-utero. In a CIRM supported study, Dr. Tippi Mackenzie and Dr. Quoc-Hung Nguyen transplanted blood-forming stem cells from normal mice into fetal mice carrying the genetic mutation for Sly syndrome. The researchers were most interested to see whether these cells could reach the brain, and whether they would change into cells called microglia, immune cells that originate from blood-forming stem cells. In a normally developing fetus, once matured, microglia produce and store the necessary enzyme, as well as regulate the immune environment of the brain.
The researchers found that the stem cells were able to engraft in the brain, liver, kidney, and other organs. Furthermore, these stem cells were able to eventually turn into the appropriate cell type needed to produce the enzyme in each of the organs.
In a press release, Dr. Mackenzie talks about the impact that this potential treatment could have.
“This group of vulnerable patients has been relatively ignored in the fetal surgery world. We know these patients could potentially benefit from a number of medical therapies. So this is our first foray into treating one of those diseases.”
In the same press release, Dr. Nguyen talks about the impact of the results from this study.
“These exciting findings are just the tip of the iceberg. They open up a whole new approach to treating a range of diseases. At the same time, there’s also a lot of work to do to optimize the treatment for humans.”
The next step for Dr. Mackenzie is to apply to the U.S. Food and Drug Administration to launch a clinical trial of enzyme replacement therapy that will ultimately enroll patients with Sly syndrome and related metabolic disorders.
This approach is similar to a CIRM funded trial conducted by Dr. Mackenzie that involves a blood stem cell transplant in utero.
The full results to this study were published in Science Translational Medicine.
By Kelly Shepard, PhD., CIRM’s Associate Director, Discovery & Translation
CIRM has previously blogged about advances in treating certain forms of “bubble baby” disease”, where a person is born with a defect in their blood forming stem cells that results in a deficient immune system, rendering them vulnerable to lethal infections by all manner of bacteria, virus or germ.
If a suitable donor can be found, or if the patient’s own defective cells can be corrected through gene therapy approaches, it is now possible to treat or cure such disorders through a bone marrow transplant. In this procedure, healthy blood stem cells are infused into the patient, taking up residence in his or her bone marrow and dividing to give rise to functioning immune cells such as T cells and B cells.
Unfortunately, there is another type of “bubble baby” disease that cannot be treated by providing healthy blood stem cells, because the defective immune system is caused by a different culprit altogether- a missing or dysfunctional thymus.
T Cells Go to School
What is a thymus? Most of us give little thought to this leaf-shaped organ, which is large and important in our early childhoods, but becomes small and inconspicuous as we age. This transformation belies the critical role a thymus plays in the development of our adaptive immune systems, which takes place in our youth: to prepare our bodies to fight infections for the rest of our lives.
One might think of the thymus as a “school”, where immature T cells go to “learn” how to recognize and attack foreign antigens (surface markers), such as those found on microorganisms or tissues from other individuals. The thymus also “teaches” our immune system to distinguish “self” from “other” by eliminating any T cells that attack our own tissues. Without this critical function, our immune system could inadvertently turn against us, causing serious autoimmune disorders such as ulcerative colitis and myasthenia gravis.
Many children with a severely deficient or absent thymus, referred to as athymia, have inherited a chromosome that is missing a key stretch of genes on a region called 22q11. Doctors believe perhaps 1/2000-1/4000 babies are born with some type of deletion in this region, which leads to a variable spectrum of disorders called 22q11 syndrome that can affect just about any part of the body, and can even cause learning disabilities and mental illness.
Individuals with one form of 22q11, called DiGeorge Syndrome, are particularly affected in the heart, thymus, and parathyroid glands. In the United States, about 20 infants are born per year with the “complete” and most severe form of DiGeorge Syndrome, who lack a thymus altogether, and have severely depressed numbers of T cells for fighting infections. Without medical intervention, this condition is usually fatal by 24 months of age.
Optimism and Setback
Although there are no therapies approved by the Food and Drug Administration (FDA) for pediatric athymia, Dr. Mary Louise Markert at Duke University and Enzyvant, Inc. have been pioneering an experimental approach to treat children with complete DiGeorge syndrome.
In this procedure, discarded thymic tissues are collected from infants undergoing cardiac surgery, where some of the thymus needs to be removed in order for the surgeon to gain access to the heart. These tissues are processed to remove potentially harmful donor T cells and then transplanted into the thigh of an athymic DiGeorge patient.
Results from early clinical trials seemed promising, with more than 70% of patients surviving, including several who are now ten years post-transplant. Based on those results, in June of 2019 Enzyvant applied to the FDA for a Biologics License Application (BLA), which is needed to be able to sell the therapy in the US. Unfortunately, only a few months later, Enzyvant announced that the FDA had declined to approve the BLA due to manufacturing concerns.
While it may be possible to address these issues in time, the need to step back to the drawing board was a devastating blow to the DiGeorge Community, who have waited decades for a promising treatment to emerge on the horizon.
Despite the setback, there is reason to hope. In early 2019, CIRM granted a “Quest” Award to team of investigators at Stanford University to develop a novel stem cell based approach for treating thymic deficiency. Co-led by Katja Weinacht, a pediatric hematologist/oncologist, and Vittorio Sebastiano, a stem cell expert and developmental biologist, the team’s strategy is to coax induced pluripotent stem cells (iPS) in the laboratory to differentiate into thymic tissue, which could then be transplanted into patients using the route pioneered by Duke and Enzyvant.
The beauty of this new approach is that pluripotent stem cells are essentially immortal in culture, providing an inexhaustible supply of fresh thymic cells for transplant, thereby allowing greater control over the quality and consistency of donor tissues. A second major advantage is the possibility of using pluripotent cells from the patient him/herself as the source, which should be perfectly immune-matched and alleviate the risk of rejection and autoimmunity that comes with use of donated tissues.
Sounds easy, so what are the challenges? As with many regenerative medicine approaches, the key is getting a pluripotent stem cell to differentiate into the right type of cells in the lab, which is a very different environment than what cells experience naturally when they develop in the context of an embryo and womb, where many cells are interacting and providing complex, instructive cues to one another. The precise factors and timing all need to be worked out and in most cases, this is done with an incomplete knowledge of human development.
A second challenge relates to using cells from DiGeorge patients to produce thymic tissue, which are missing several genes on their 22nd chromosome and will likely require sophisticated genetic engineering to restore this ability.
Fortunately, Drs. Weinacht and Sebastiano are up to the challenge, and have already made progress in differentiating human induced pluripotent stem cells (iPS) into thymic lineage intermediates that appear to be expressing the right proteins at the right time. They plan to combine these cells with engineered materials to create a three-dimensional (3D) tissue that more closely resembles an authentic organ, and which can be tested for functionality in athymic mice.
There is more work to be done, but these advances, along with continued technological improvements and renewed efforts from Enzyvant, could forge a path to the clinic and lead to a brighter future for patients suffering from congenital athymia and other forms of thymic dysfunction.
This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.
But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.
The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D). Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes.
Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”
It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.
It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.
UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.
Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”
The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.
But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.
Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.
The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.
2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.
The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.
In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.
“This sequencing technique allowed us
to see all the different types of cells present at various stages of heart development
and helped us identify which genes are activated and suppressed along the way. We
were not only able to uncover the existence of unknown cell types, but we also
gained a better understanding of the function and behavior of individual
cells—information we could never access before.”
Then they partnered with a team at Luxembourg Centre for Systems
Biomedicine (LCSB) of the University of Luxembourg which ran a
computational analysis to identify which genes were involved in creating
different cell types. This highlighted one specific gene, called Hand2, that controls
the activity of thousands of other genes. They found that a lack of Hand2 in
mice led to an inability to form one of the heart’s chambers, which in turn led
to impaired blood flow to the lungs. The embryo was creating the cells needed
to form the chamber, but not a critical pathway that would allow those cells to
get where they were needed when they were needed.
Gifford says this has given us a deeper insight into how
cells are formed, knowledge we didn’t have before.
“Single-cell technologies can inform us about how organs
form in ways we couldn’t understand before and can provide the underlying cause
of disease associated with genetic variations. We revealed subtle differences
in very, very small subsets of cells that actually have catastrophic
consequences and could easily have been overlooked in the past. This is the
first step toward devising new therapies.”
These therapies are needed to help treat congenital heart
defects, which are the most common and deadly birth defects. There are more
than 2.5 million Americans with these defects. Deepak Srivastava, President of
Gladstone and the leader of the study, said the knowledge gained in this study
could help developed strategies to help address that.
to see the long-term consequences in adults, and right now, we don’t really
have any way to treat them. My hope is that if we can understand the genetic
causes and the cell types affected, we could potentially intervene soon after
birth to prevent the worsening of their state over time.
Proposition 71 is the state ballot initiative that created California’s Stem Cell Agency. This month, the Agency reached another milestone when the 71st clinical trial was initiated in the CIRM Alpha Stem Cell Clinics (ASCC) Network. The ASCC Network deploys specialized teams of doctors, nurses and laboratory technicians to conduct stem cell clinical trials at leading California Medical Centers.
These teams work with academic and industry partners to support patient-centered for over 40 distinct diseases including:
Amyotrophic Lateral Sclerosis (ALS)
Brain Injury & Stroke
Cancer at Multiple Sites
Diabetes Type 1
Eye Disease / Blindness Heart Failure
HIV / AIDS
Severe Combined Immunodeficiency (SCID)
Sickle Cell Anemia
Spinal Cord Injury
These clinical trials have treated over 400 patients and counting. The Alpha Stem Cell Clinics are part of CIRM’s Strategic Infrastructure. The Strategic Infrastructure program which was developed to support the growth of stem cell / regenerative medicine in California. A comprehensive update of CIRM’s Infrastructure Program was provided to our Board, the ICOC.
CIRM’s infrastructure catalyzes stem cell / regenerative medicine by providing resources to all qualified researchers and organizations requiring specialized expertise. For example, the Alpha Clinics Network is supporting clinical trials from around the world.
Many of these trials are sponsored by commercial companies that have no CIRM funding. To date, the ASCC Network has over $27 million in contracts with outside sponsors. These contracts serve to leverage CIRMs investment and provide the Network’s medical centers with a diverse portfolio of clinical trials to address patients’’ unmet medical needs.
Alpha Clinics – Key Performance Metrics
70+ Clinical Trials
400+ Patients Treated
40+ Disease Indications
Over $27 million in contracts with commercial sponsors
The CIRM Alpha Stem Cell Clinics and broader Infrastructure Programs are supporting stem cell research and regenerative medicine at every level, from laboratory research to product manufacturing to delivery to patients. This infrastructure has emerged to make California the world leader in regenerative medicine. It all started because California’s residents supported a ballot measure and today we have 71 clinical trials for 71.
Hunter syndrome is devastating. It’s caused by a single enzyme, IDS, that is either missing or malfunctioning. Without the enzyme the body is unable to break down complex sugar molecules and as those build up they cause permanent, progressive damage to the body and brain and, in some instances, result in severe mental disabilities. There is no cure and existing treatments are limited and expensive.
But now researchers at the University of Manchester in England have developed an approach that could help children – the vast majority of them boys – suffering from Hunter syndrome.
Working with a mouse model of the disease the researchers took some blood stem cells from the bone marrow and genetically re-engineered them to correct the mutation that caused the problem. They also added a “tag” to the IDS enzyme to help it more readily cross the blood brain barrier and deliver the therapy directly to the brain.
In a news release Brian Bigger, the lead researcher of the study published in EMBO Molecular Medicine, said the combination therapy helped correct bone, joint and brain disease in the mice.
“We expected the stem cell gene therapy approach to deliver IDS enzyme to the brain, as we have shown previously for another disease: Sanfilippo types A and B, but we were really surprised to discover how much better the tag made the therapy in the brain. It turns out that the tag didn’t only improve enzyme uptake across the blood brain barrier, but also improved uptake of the enzyme into cells and it appeared to be more stable in the bloodstream – all improvements on current technology.”
While the results are very encouraging it is important to remember the experiment was done in mice. So, the next step is to see if this might also work in people.
Joshua Davies has made a video highlighting the impact Hunter syndrome has on families: it’s called ‘Living Beyond Hope’
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.
“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. 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.
Stem Cell Image of the Week: Obesity-in-a-dish reveals mutations and abnormal function in nerve cells
Image shows two types of hypothalamic neurons (in magenta and cyan) that were derived from human induced pluripotent stem cells. Credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute
Our stem cell image of the week looks like the work of a pre-historic cave dweller who got their hands on some DayGlo paint. But, in fact, it’s a fluorescence microscopy image of stem cell-derived brain cells from the lab of Dhruv Sareen, PhD, at Cedars-Sinai Medical Center. Sareen’s team is investigating the role of the brain in obesity. Since the brain is a not readily accessible organ, the team reprogrammed skin and blood cell samples from severely obese and normal weight individuals into induced pluripotent stem cells (iPSCs). These iPSCs were then matured into nerve cells found in the hypothalamus, an area of the brain that regulates hunger and other functions.
A comparative analysis showed that the nerve cells derived from the obese individuals had several genetic mutations and had an abnormal response to hormones that play a role in telling our brains that we are hungry or full. The Cedars-Sinai team is excited to use this obesity-in-a-dish system to further explore the underlying cellular changes that lead to excessive weight gain. Ultimately, these studies may reveal ways to combat the ever-growing obesity epidemic, as Dr. Sareen states in a press release:
“We are paving the way for personalized medicine, in which drugs could be customized for obese patients with different genetic backgrounds and disease statuses.”
Differences found in stem cells derived from male vs female.
Microscope picture of a colony of iPS cells. Credit: Vincent Pasque
Scientists at UCLA and KU Leuven University in Belgium carried out a study to better understand the molecular mechanisms that control the process of reprogramming adult cells back into the embryonic stem cell-like state of induced pluripotent stem cells (iPSCs). Previous studies have shown that female vs male embryonic stem cells have different patterns of gene regulation. So, in the current study, male and female cells were analyzed side-by-side during the reprogramming process. First author Victor Pasquale explained in a press release that the underlying differences stemmed from the sex chromosomes:
In a normal situation, one of the two X chromosomes in female cells is inactive. But when these cells are reprogrammed into iPS cells, the inactive X becomes active. So, the female iPS cells now have two active X chromosomes, while males have only one. Our results show that studying male and female cells separately is key to a better understanding of how iPS cells are made. And we really need to understand the process if we want to create better disease models and to help the millions of patients waiting for more effective treatments.”
Using mini-brains and CRISPR to study genetic linkage of schizophrenia, depression and bipolar disorder.
If you haven’t already picked up on a common thread in this week’s stories, this last entry should make it apparent: iPSC cells are the go-to method to gain insight in the underlying mechanisms of a wide range of biology topics. In this case, researchers at Brigham and Women’s Hospital at Harvard Medical School were interested in understanding how mutations in a gene called DISC1 were linked to several mental illnesses including schizophrenia, bipolar disorder and severe depression. While much has been gleaned from animal models, there’s limited knowledge of how DISC1 affects the development of the human brain.
The team used human iPSCs to grow cerebral organoids, also called mini-brains, which are three-dimensional balls of cells that mimic particular parts of the brain’s anatomy. Using CRISPR-Cas9 gene-editing technology – another very popular research tool – the team introduced DISC1 mutations found in families suffering from these mental disorders.
Compared to cells with normal copies of the DISC1 gene, the mutant organoids showed abnormal structure and excessive cell signaling. When an inhibitor of that cell signaling was added to the growing mutant organoids, the irregular structures did not develop.
These studies using human cells provide an important system for gaining a better understanding of, and potentially treating, mental illnesses that victimize generations of families.
In honor of brain awareness week, our featured stem cell photo is of the brain! Scientists at the Massachusetts General Hospital and Harvard Stem Cell Institute identified a genetic switch that could potentially improve memory during aging and symptoms of PTSD. Shown in this picture are dentate gyrus cells (DGC) (green) and CA3 interneurons (red) located in the memory-forming area of the brain known as the hippocampus. By reducing the levels of a protein called abLIM3 in the DGCs of older mice, the researchers were able to boost the connections between DGCs and CA3 cells, which resulted in an improvement in the memories of the mice. The team believes that targeting this protein in aging adults could be a potential strategy for improving memory and treating patients with post-traumatic stress disorder (PTSD). You can read more about this study in The Harvard Gazette.
New target for obesity. Fat cells typically get a bad rap, but there’s actually a type of fat cell that is considered “healthier” than others. Unlike white fat cells that store calories in the form of energy, brown fat cells are packed with mitochondria that burn energy and produce heat. Babies have brown fat, so they can regulate their body temperature to stay warm. Adults also have some brown fat, but as we get older, our stores are slowly depleted.
In the fight against obesity, scientists are looking for ways to increase the amount of brown fat and decrease the amount of white fat in the body. This week, CIRM-funded researchers from the Salk Institute identified a molecule called ERRg that gives brown fat its ability to burn energy. Their findings, published in Cell Reports, offer a new target for obesity and obesity-related diseases like diabetes and fatty liver disease.
The team discovered that brown fat cells produce the ERRg molecule while white fat cells do not. Additionally, mice that couldn’t make the ERRg weren’t able to regulate their body temperature in cold environments. The team concluded in a news release that ERRg is “involved in protection against the cold and underpins brown fat identity.” In future studies, the researchers plan to activate ERRg in white fat cells to see if this will shift their identity to be more similar to brown fat cells.
Mice that lack ERR aren’t able to regulate their body temperature and are much colder (right) than normal mice (left). (Image credit Salk Institute)
Tale of two nanomedicine stories: making gene therapies more efficient with a bit of caution (Todd Dubnicoff). This week, the worlds of gene therapy, stem cells and nanomedicine converged for not one, but two published reports in the journal American Chemistry Society NANO.
The first paper described the development of so-called nanospears – tiny splinter-like magnetized structures with a diameter 5000 times smaller than a strand of human hair – that could make gene therapy more efficient and less costly. Gene therapy is an exciting treatment strategy because it tackles genetic diseases at their source by repairing or replacing faulty DNA sequences in cells. In fact, several CIRM-funded clinical trials apply this method in stem cells to treat immune disorders, like severe combined immunodeficiency and sickle cell anemia.
This technique requires getting DNA into diseased cells to make the genetic fix. Current methods have low efficiency and can be very damaging to the cells. The UCLA research team behind the study tested the nanospear-delivery of DNA encoding a gene that causes cells to glow green. They showed that 80 percent of treated cells did indeed glow green, a much higher efficiency than standard methods. And probably due to their miniscule size, the nanospears were gentle with 90 percent of the green glowing cells surviving the procedure.
As Steve Jonas, one of the team leads on the project mentions in a press release, this new method could bode well for future recipients of gene therapies:
“The biggest barrier right now to getting either a gene therapy or an immunotherapy to patients is the processing time. New methods to generate these therapies more quickly, effectively and safely are going to accelerate innovation in this research area and bring these therapies to patients sooner, and that’s the goal we all have.”
While the study above describes an innovative nanomedicine technology, the next paper inserts a note of caution about how experiments in this field should be set up and analyzed. A collaborative team from Brigham and Women’s Hospital, Stanford University, UC Berkeley and McGill University wanted to get to the bottom of why the many advances in nanomedicine had not ultimately led to many new clinical trials. They set out looking for elements within experiments that could affect the uptake of nanoparticles into cells, something that would muck up the interpretation of results.
imaging of female human amniotic stem cells incubated with nanoparticles demonstrated a significant increase in uptake compared to male cells. (Green dots: nanoparticles; red: cell staining; blue: nuclei) Credit: Morteza Mahmoudi, Brigham and Women’s Hospital.
In this study, they report that the sex of cells has a surprising, noticeable impact on nanoparticle uptake. Nanoparticles were incubated with human amniotic stem cells derived from either males or females. The team showed that the female cells took up the nanoparticles much more readily than the male cells. Morteza Mahmoudi, PhD, one of the authors on the paper, explained the implications of these results in a press release:
“These differences could have a critical impact on the administration of nanoparticles. If nanoparticles are carrying a drug to deliver [including gene therapies], different uptake could mean different therapeutic efficacy and other important differences, such as safety, in clinical data.”
Adrienne Shapiro will tell you that she’s just a mom.
And it’s true. She is just a mom. Just a mom who is the fourth generation of mothers in her family to have children born with sickle cell disease. Just a mom who was an early advocate of innovative stem cell and gene therapy research by UCLA scientist Dr. Don Kohn which has led to an on-going, CIRM-funded clinical trial for sickle cell disease. Just a mom who is the patient advocate representative on a Clinical Advisory Panel (CAP) that CIRM is creating to help guide this clinical trial.
She’s just a mom who has become a vocal stem cell activist, speaking to various groups about the importance of CIRM’s investments in both early stage research and clinical trials. She’s just a mom who was awarded a Stem Cell and Regenerative Medicine Action Award at last month’s World Stem Cell Summit. She’s just a mom who, in her own words, “sees a new world not just for her children but for so many other children”, through the promise of stem cell therapies.
Yep, she’s just a mom. And it’s the tireless advocacy of moms like Adrienne that will play a critical role in accelerating stem cell therapies to patients with unmet medical needs. We can use all the moms we can get.
Adrienne Shapiro speaks to the CIRM governing Board about her journey as a patient advocate