Gladstone scientists respond to coronavirus pandemic

In these uncertain times, we often look to our top scientists for answers as well as potential solutions. But where does one begin to try and solve a problem of this magnitude? The first logical step is building on the supplies currently available, the work already accomplished, and the knowledge acquired.

This is the approach that the Gladstone Institutes in San Francisco is taking. Various scientists at this institution have shifted their current operations towards helping with the current coronavirus pandemic. These efforts have focused on helping with diagnostics, treatment, and prevention of COVID-19.

Diagnostics

Dr. Jennifer Doudna and Dr. Melanie Ott are collaborating in order to develop an effective method to rapidly diagnose those with COVID-19. Dr. Doudna’s work has focused on CRISPR technology, which we have talked about in detail in a previous blog post, while Dr. Ott has focused on studying viruses. By combining their expertises, these two scientists hope to develop a diagnostic tool capable of delivering rapid results and usable in areas such as airports, ports of entry, and remote communities.

Treatment

Dr. Nevan Krogan has discovered all of the human host cell proteins that COVID-19 interacts with to hijack the cell’s machinery. These proteins serve as new targets for potential drug therapies.

Since the high fatality rate of the virus is driven by lung and heart failure, Dr. Ott, Dr. Bruce Conklin, and Dr. Todd McDevitt will test effects of the virus and potential drug therapies in human lung organoids and human heart cells, both developed from human stem cells.

Dr. Warner Greene, who also focuses on the study of viruses, is screening a variety of FDA-approved drugs to identify those that could be rapidly repurposed as a treatment for COVID-19 patients or even as a preventive for high risk-groups.

Prevention

Dr. Leor Weinberger has developed a new approach to fight the spread of viruses. It is called therapeutic interfering particles (TIPs) and could be an alternative to a vaccine. TIPs are defective virus fragments that mimic the virus but are not able to replicate. They combat the virus by hijacking the cell machinery to transform virus-infected cells into factories that produce TIPS, amplifying the effect of TIPs in stopping the spread of virus. TIPs targeting COVID-19 would transmit along the same paths as the virus itself, and thus provide protection to even the most vulnerable populations.

You can read more about these groundbreaking projects in the news release linked here.

A recap on last week: two gut wrenching studies

Fluorescent pictures of a human colon organoid
Image credit: Dr Thierry Jarde

With everyone stocking up on food essentials this past week, it brings to mind the vital role that our stomach plays in order to properly digest these foods. This week, we wanted to share two separate studies related to aspects of the gut.

Promising results for a gut-related condition

Gastroparesis is a painful condition in which the stomach is unable to empty itself of food. Symptoms include heartburn, abdominal cramps, nausea, vomiting, and feeling full quickly when eating. In extremely severe cases, patients can experience dehydration, malnutrition and bezoars, a small stone-like matter that forms when food hardens and can block the opening from the stomach into the pylorus (small intestine).

A new study, led by Dr. Prabhash Dadhich and Dr. Khalil N Bitar at Wake Forest School of Medicine showed how a stem cell-combo therapy could bring long-term relief to these patients.

The team of scientists used interstitial cells of Cajal (ICCs), a type of stem cell found in the gastrointestinal tract, in combination with neural stem cells. An animal model similar to gastroparesis was then made using tissue from the small intestine of rats. The combination of stem cells were then injected into the small intestine tissue, where the cells were able to survive and integrate with host muscle layers.

In a news release, Dr. Bitar explains how this approach could potentially restore stomach muscle function and enable normal food digestion.

“Our analysis also confirmed the reinstatement and restoration of the stomach muscles’ functionality, both of which are critical in the treatment of pylorus dysfunctionality. These findings are very promising. We hope this study opens avenues for future cell-based clinical applications.”

The full study was published in Stem Cells Journals.

Superbug can damage stem cells in the gut

Clostridioides difficile (C. diff)
Image courtesy of the Central for Disease Control (CDC) website

A collaboration by the Monash Biomedicine Discovery Institute (BDI) has revealed that a bacterial superbug can prevent stem cells in the gut from regenerating the inner lining of the intestine.

Clostridioides difficile (C. diff) is a bacterial germ that is responsible for more than half of all hospital infections related to the gut and causes severe diarrhea. It usually grows after antibiotic treatment is administered to a patient.

The team of scientists found that C. diff damages stem cells in the colon, which in turn can cause problems with tissue repair and recovery.

In a press release, Professor Helen Abud, an expert in stem cell biology and one of the authors of this study, explains how this discovery can have wider implications.

“Our study provides the first direct evidence that a microbial infection alters the functional capacity of gut stem cells. It adds a layer of understanding about how the gut repairs after infection and why this superbug can cause the severe damage that it does. The reason it’s important to have that understanding is that we’re rapidly running out of antibiotics – we need to find other ways to prevent and treat these infections.”

The full results to this study were published in Proceedings of the National Academy of Sciences (PNAS).

New hydrogel developed could aid in therapies to generate bones in head and neck

Taking a cue from mussels’ natural ability to adhere to surfaces underwater, the UCLA researchers incorporated an alginate-based solution in their hydrogel.
Photo taken by D. Jude, Univ. of Michigan

When most people think of mussels, what immediately comes to mind might be a savory seafood dish or favorite seafood restaurant. But to Dr. Alireza Moshaverinia and his team of researchers at the UCLA School of Dentistry, it’s the ability that mussels have to stick to wet surfaces that is of particular interest.

Partially inspired by this concept and with support from CIRM, the team of researchers developed the first adhesive hydrogel specifically to regenerate bone and tissue defects following head and neck injuries.

Over the past few years, surgeons and clinicians have began to use hydrogels to administer stem cells to help regenerate lost tissues and for bone defects. Hydrogels are beneficial because they can be effective at carrying stem cells to targeted areas inside the body. However, when used in surgeries of the mouth, they tend to become less effective because blood and saliva prevent them from properly adhering to the targeted site. As a result of this, the stem cells don’t stay in place long enough to deliver their regenerative properties.

To help with this problem, the researchers at UCLA developed a new hydrogel by adding alginate into the mix. Alginates are found in the cells of algae and form a sticky, gum-like substance when wet.

The scientists then tested their new hydrogel by loading it with bone building stem cells and applying it to the mouths of rats with an infectious disease that affects the bone structure. They then sealed the hydrogel in place and applied a light treatment, similar to what dentists use in humans to solidify dental fillings.

The results showed that the bone around the implants in all of the rats had completely regenerated.

In a news release from UCLA, Dr. Moshaverinia elaborates on what this study means for potential future treatments.

“The light treatment helped harden the hydrogel, providing a more stable vehicle for delivery of the stem cells. We believe that our new tissue engineering application could be an optimal option for patients who have lost their hard and soft craniofacial tissues due to trauma, infection or tumors.”

The full study was published in Science Translational Medicine.

CIRM-funded trial for blood cancer releases promising new data


A CIRM-funded trial conducted by Oncternal Therapeutics in collaboration with UC San Diego released an interim clinical data update for patients with mantle cell lymphoma (MCL), a type of blood cancer.

The treatment being developed involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the blood cancer and makes it more vulnerable to anti-cancer drugs.

Here are the highlights from the new interim clinical data:

  • Patients had received a median of two prior therapies before participating in this study including chemotherapy; autologous stem cell transplant (SCT); autologous SCT and CAR-T therapy; autologous SCT and allogeneic SCT; and ibrutinib with rituximab, a different type of antibody therapy.
  • 6 of the 12 patients in the trial experienced a Complete Response (CR), which is defined as the disappearance of all signs of cancer in response to treatment.
  • All six CRs are ongoing, including one patient who has remained in CR for more than 21 months past treatment.
  • Four of the six patients achieved CRs within four months on the combination of cirmtuzumab and ibrutinib.
  • Of the remaining 6 patients, 4 experienced a Partial Response (PR), which is defined as a decrease in the extent of the cancer in the body.
  • The remaining two patients experienced Stable Disease (SD), which is defined as neither an increase or decrease in the extent of the cancer.

The full interim clinical data update can be viewed in the press release here.

CIRM-funded treatment for Cystinosis receives orphan drug designation

Dr. Stephanie Cherqui, UC San Diego

Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.

Fortunately for us, a stem cell-gene therapy approach used in a CIRM-funded clinical trial for Cystinosis has just received orphan drug designation. The trial is being conducted by Dr. Stephanie Cherqui at UC San Diego, which is an academic collaborator for AVROBIO, Inc.

Cystinosis is a rare disease that primarily affects children and young adults, and leads to premature death, usually in early adulthood.  Patients inherit defective copies of a gene called CTNS, which results in abnormal accumulation of an amino acid called cystine in all cells of the body.  This buildup of cystine can lead to multi-organ failure, with some of earliest and most pronounced effects on the kidneys, eyes, thyroid, muscle, and pancreas.  Many patients suffer end-stage kidney failure and severe vision defects in childhood, and as they get older, they are at increased risk for heart disease, diabetes, bone defects, and neuromuscular defects. 

Dr. Cherqui’s clinical trial uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. The goal of this treatment is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.  

In an earlier blog, we shared a story by UCSD news that featured Jordan Janz, the first patient to participate in this trial, as well as the challenges promising approaches like this one face in terms of getting financial support. Our hope is that in addition to the funding we have provided, this special designation gives additional support to what appears to be a very promising treatment for a very rare disease.

You can read the official press release from AVROBIO, Inc. related to the orphan drug designation status here.

New CAR-T cell therapy using scorpion venom developed to treat brain tumors

Contributed by Wikimedia Commons (Public Domain)

Glioblastoma (GBM) is an aggressive form of cancer that begins in the brain and results in tumors that can be very difficult to treat. This condition has claimed the lives of Beau Biden, former Vice President Joe Biden’s son, and John McCain, former Senator of Arizona. However, a new approach to combat this condition is being developed at City of Hope and has just received approval from the FDA to conduct clinical trials. The innovative approach involves using a combination of chimeric antigen receptor (CAR)-T cell therapy and specific components of scorpion venom!

Before we dive into how the scorpion venom is being used, what exactly is CAR-T cell therapy?

Diagram of CAR-T Cell Therapy
Image Source: National Cancer Institute

This approach consists of using T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them with a protein called a chimeric antigen receptor (CAR). These newly designed CAR-T cells are able to identify and destroy cancer cells by detecting a specific protein on these cells. What makes CAR-T cell even more promising is that the specific protein detected can be set to virtually anything.

This is where the scorpion venom comes into play. One of the components of this venom is called chlorotoxin (CLTX), which has the ability to specifically bind to brain tumor cells.

Michael Barish, Ph.D. (Left), Christine Brown, Ph.D. (Center), Dongrui Wang (Right)
Photo Credit: Business Wire

For this study, Dr. Christine Brown, Dr. Michael Barish, and a team of researchers at City of Hope designed CAR-T cells using chlorotoxin in order to specifically detect and destory brain tumor cells. Now referred to as CLTX-CAR-T cells, they found that these newly engineered cells were highly effective at selectively killing brain tumor cells in animal models. What’s more remarkable is that the CLTX-CAR-T cells ignored non-tumor cells in the brain and other organs.

In a press release, Dr. Barish describes the CLTX-CAR-T cell approach in more detail.

“Much like a scorpion uses toxin components of its venom to target and kill its prey, we’re using chlorotoxin to direct the T cells to target the tumor cells with the added advantage that the CLTX-CAR T cells are mobile and actively surveilling the brain looking for appropriate target. We are not actually injecting a toxin, but exploiting CLTX’s binding properties in the design of the CAR. The idea was to develop a CAR that would target T cells to a wider variety of GBM tumor cells than the other antibody-based CARs.”

In the same press release, Dr. Brown talks about the promise of this newly developed therapy.

“Our chlorotoxin-incorporating CAR expands the populations of solid tumors potentially targeted by CAR T cell therapy, which is particularly needed for patients with cancers that are difficult to treat such as glioblastoma. This is a completely new targeting strategy for CAR T therapy with CARs incorporating a recognition structure different from other CARs.”

The first-in-human clinical trial using the CLTX-CAR T cells is now screening potential patients.

CIRM has funded a separate clinical trial conducted by Dr. Brown that also involves CAR-T cell therapy for brain tumors.

The full results of this study was published in Science Translational Medicine.

A video talking about this approach can also be found here.

Stem cell transplant in utero offers potential treatment for congenital diseases

Dr. Tippi Mackenzie, UCSF
Image Credit: UCSF

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.

Stem cells transplanted in utero (green) engrafted into fetal mouse brain tissue. 
Image credit: Q-H Nguyen/MacKenzie lab.

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.

Overcoming obstacles in blood stem cell therapies

Photo Credit: OHSU Knight Cancer Institute

Today, we here at CIRM wanted to provide an update on the fascinating world of hematopoietic (blood) stem cell-based therapies.  What is the current status of this promising field and what are some of the challenges that need to be overcome? Dr. Kelly Shepard, Associate Director of Discovery and Translation here at CIRM, answers these questions and many more in the blog entry below.

There have been a number of exciting advances in regenerative medicine over the past few years, especially in the use of gene therapy and hematopoietic (blood) stem cell transplantation to treat and even cure various diseases of the blood and immune system. These studies built off groundbreaking research by Till and McCulloch in the 1950-60’s, who identified a rare and special stem cell in the bone marrow of mice that gives rise to all cells of the blood and immune system for the lifetime of the animal, the “hematopoietic stem cell”, or HSC. It wasn’t long before scientists and doctors realized the therapeutic implications of this discovery, and the journey to identify the human counterpart began. Fast forward to the present, and HSC transplantation (HSCT) has become a standard medical procedure for treating various cancers and genetic disorders of the blood. The basic premise is this: a patient with a diseased or defective blood/immune system receives an infusion of healthy HSCs, which are typically procured from donated bone marrow or umbilical cords, but in certain situations, might come from the patient him/herself. Once established in the recipient, these healthy cells will divide and regenerate a new blood and immune system over the course of the patient’s lifetime.

For HSCT to be successful, the donor cells must “engraft”, or take up permanent residence in their new environment. This usually necessitates “conditioning” the recipient with some form of chemotherapy or radiation, which eliminates some of the patient’s own cells to create room for the new arrivals. Unfortunately, conditioning creates a situation where the patient is extremely vulnerable to infections and other complications during the period of recovery, as it will take weeks for his/her blood and immune systems to be reestablished. These inherent risks mean HSC transplants can only be offered to patients with life threatening diseases such as leukemia, or to those with significant blood/immune disorders who are sufficiently healthy to tolerate the toxic conditioning regimen and to weather the extended period of recovery.

A second major issue preventing a more widespread use of HSCT is the shortage of healthy donor HSCs that are available for transplant, which must be immune matched to the recipient to prevent rejection. Immune matching is also critical to avoid a dangerous complication called graft vs. host disease, where the transplanted cells or their progeny launch an immune attack against the recipient’s organs, often leading to chronic disease and sometimes, death. Unfortunately, there are many people who have no compatible donors and for whom the risk of even a partially matched transplant is unacceptable.

Scientists and clinicians have long sought means to overcome the technical challenges of HSCT in order to “unleash” its true potential to cure and treat a wider variety of diseases, and to  make it feasible (and affordable) for a much larger number of patients. CIRM has endeavored to support novel approaches that could hopefully produce game changing advances for the field. Some of these approaches were recently highlighted in a Perspective article, published in Stem Cells Translational Medicine in early 2020, along with a discussion of other important advances in related areas, listed below. More information can be found in that article or referring to our website to learn more about the individual projects.

Approaches that could increase the availability of healthy HSCs for transplant include development of non-toxic conditioning regimens to facilitate a patient’s acceptance and recovery from the transplant procedure; novel technologies for expanding HSCs for transplant; and gene modification technologies to correct inherited mutations in HSCs.
Illustration Credit: Dr. Kelly Shepard, CIRM

Developing New Sources of Healthy and Immune Compatible HSCs for transplant

  • Exploring ways to produce HSCs from pluripotent stem cells in the lab
  • Expanding populations of HSCs that are already present in donated tissues such as cord blood
  • Using genetic engineering to “repair” defects in the DNA of HSCs from patients with inherited blood and/or immune disorders
  • Using genetic engineering to create “immune invisible” or “universal donor” HSCs that will not be rejected after transplantation

Developing Safer and More Tolerable Conditioning Regimens

  • Exploring reduced intensity forms of conditioning with drugs or radiation
  • Using antibodies rather than chemicals to free up space in the bone marrow for incoming, donor HSCs
  • Using dietary methods to free up space in the bone marrow for incoming, donor HSCs

Accelerating Reovery of Immune Function Lost Through Conditioning

  • Adding back key populations of immune cells to protect the host during regeneration of their immune system
  • Discovering new drugs and treatments to accelerate the pace of regeneration after transplant, or to prevent the death of HSCs that survived conditioning

Overcoming these scientific and technical challenges could create a paradigm shift in the way HSCT is applied and used and consequently, reduce the costs and risks associated with the procedure. In this way, the true potential of HSCT could be unleashed for the greatest good.

CIRM supported study finds that a gene associated with autism influences brain stem cells

Dr. Bennett Novitch, UCLA Broad Stem Cell Research Center
Image Credit: UCLA Broad Stem Cell Research Center

In a previous blog post, we discussed new findings in a CIRM supported study at the Salk Institute for Autism Spectrum Disorder (ASD), a developmental disorder that comes in broad ranges and primarily affects communication and behavior.

This week, a new study, also supported by CIRM, finds that a gene associated with ASD, intellectual disability, and language impairment can affect brain stem cells, which in turn, influence early brain development. Dr. Bennett Novitch and his team at UCLA evaluated a gene, called Foxp1, which has been previously studied for its function in the neurons in the developing brain.

Image showing brain cells with lower levels of Foxp1 function (left) and higher levels (right). neural stem cells are stained in green; secondary progenitors and neurons in red.
Image Credit: UCLA Broad Stem Cell Research Center

In this study, Dr. Novitch and his team looked at Foxp1 levels in the brains of developing mouse embryos. What they discovered is that, in normal developing mice the gene was active much earlier than previous studies had indicated. It turns out that the gene was active during the period when neural stem cells are just beginning to expand in numbers and generate a subset of brain cells found deep within the developing brain.

When mice lacked the gene entirely, there were fewer neural stem cells at early stages of brain development, as well as fewer brain cells deep within the developing brain. Alternatively, when the levels of the gene were above normal, the researchers found significantly more neural stem cells and brain cells deep within the developing brain. Additionally, higher levels of the neural stem cells were observed in mice with high levels of the gene even after they were born.

In a press release from UCLA, Dr. Novitch explains how the different levels of the gene can be tied to the variation of Foxp1 levels seen in ASD patients.

“What we saw was that both too much and too little Foxp1 affects the ability of neural stem cells to replicate and form certain neurons in a specific sequence in mice. And this fits with the structural and behavioral abnormalities that have been seen in human patients.”

The full study was published in Cell Reports.

CIRM funded study links rapid brain growth in autism to DNA damage

Meiyan Wang and Dr. Rusty Gage at the Salk Institute.
Image Credit: Salk Institute

Autism spectrum disorder (ASD), is a developmental disorder that comes in broad ranges and primarily affects communication and behavior. Many people with ASD also have macrocephaly, or unusually large heads. Unfortunately, understanding the underlying causes of this disorder and development of potential treatments has been slow.

However, Dr. Rusty Gage and his team at the Salk Institute in San Diego have discovered a unique pattern of DNA damage in brain cells derived from individuals with macrocephalic (larger than normal head) ASD.

In a previous study, Dr. Gage and his team discovered that brain stem cells in people with macrocephalic ASD grew more quickly compared to normal individuals. Brain stem cells have the ability to turn into various kind of cell types in the brain such as neurons. This finding led them to the possibly that the rapid growth of brain stem cells in people with macrocephalic ASD could lead to larger than normal brains.

In the current study, they continue their work by looking more closely at neural precursor cells (NPC), a certain type of brain stem cell. The researchers collected skin cells from individuals with marcocephalic ASD and normal individuals and used stem-cell reprogramming to turn these cells back into NPCs.

Cells that will eventually become neurons (brain stem cells) derived from individuals with autism spectrum disorder, shown in the right panel, exhibit increased DNA damage (shown in the red stain), compared to those derived from healthy individuals (left panel).
Image Credit: Salk Institute

As NPCs replicate and mature, it is normal for their DNA to accumulate small errors, most of which are corrected and never do any harm. But the researchers discovered that the NPCs they derived from macrocephalic ASD individuals acquired significantly higher levels of DNA damage compared to those derived from normal individuals. Furthermore, they found that the DNA damage was clustered around various genes that have been linked to ASD in separate studies.

In a news release, Dr. Gage commented on the impact of DNA damage during the cell replication process.

“Division, or replication, is one of the most dangerous things that a cell can do. Most DNA damage is repaired through a remarkably efficient repair process, but errors occur when the rate of division is altered genetically or environmentally, which can lead to long term functional defects.”

In the same news release, graduate student Meiyan Wang and first author of this study elaborates on these results and the future direction of this work.

“What the new results are telling us is that cells from people with macrocephalic autism not only proliferate more but naturally experience more replication stress. We’d like to look deeper at how replication stress and DNA damage affects neuronal function in the long term and whether adult neurons arising from these stem cells have more mutations than usual.”

The full results of this study were published in Cell Stem Cell.