Avoiding the hippocampus during whole-brain radiotherapy prevents cognitive side effects (Adonica Shaw)

Whole-brain radiotherapy can be delivered more safely to patients with brain metastases by avoiding the hippocampus according to a new phase III trial.

At the beginning of the study, scientists hypothesized that radiation to the hippocampal stem cells played a role in cognitive decline. 500 patients were randomized to whole brain radiotherapy, some with and without hippocampal avoidance. The results of the clinical trial found a 26% relative reduction in risk of cognitive toxicity following whole brain radiation therapy with hippocampal avoidance versus whole brain radiotherapy. The cognitive function benefit of hippocampal avoidance did not differ by age.

“This study demonstrates that we can deliver whole brain radiotherapy with similar cognitive outcomes as radiosurgery,” said lead author and co-principal investigator of the phase III trial Vinai Gondi, MD, director of research at the Northwestern Medicine Chicago Proton Center and co-director of the Brain Tumor Center at Northwestern Medicine Cancer Center Warrenville. “These trial results revolutionize our understanding of the cognitive effects of brain irradiation in a manner that has far-reaching implications in terms of the safer radiotherapy treatment of primary or metastatic brain tumors.”

Brain metastases, cancer cells that have spread to the brain from primary tumors in other organs, is one of the most common cancer conditions managed by radiation oncologists. Due to concerns about cognitive decline, whole brain radiotherapy is currently often the last resort, even though it is one of the most effective treatments for brain metastases.

By establishing that the hippocampal region is sensitive to radiation, treatment plans for brain metastases or other brain tumors can employ advanced techniques such as intensity-modulated radiation therapy (IMRT) or proton therapy to reduce dose to the hippocampus and offer brain therapy with less toxicity.

Better model to help speed up new drugs for schizophrenia (Kevin McCormack)

One of the problems in developing new treatments for diseases is finding a model that accurately reflects how a new treatment might work in people. Typically, we’ll test some new approach on a mouse model of a disease, to see if it is safe and works. But often what works in a mouse doesn’t work in people. Now a new study in the journal Nature Communications may have found a better model to test drugs for people with schizophrenia.

Right now, all antipsychotic drugs approved by the Food and Drug Administration (FDA) for schizophrenia target one specific dopamine receptor in the brain. Dopamine is a chemical that acts as a messenger in the brain and it’s thought that imbalances in this receptor are a leading cause of schizophrenia. However, around two-thirds of people with the condition don’t respond to the medications that target this receptor.

So, researchers at the Icahn School of Medicine at Mount Sinai, Eli Lilly and Company, and Sema4 thought that maybe a better way to test potential new medications would be on cells that came from people who actually have schizophrenia, rather than a mouse.

They took cells from 12 people with schizophrenia and 12 healthy people, and turned those cells into neural progenitor cells, the kind of brain cell affected by the disease. They then tested those cells against 135 different medications and found that the patient-derived cells provided lots more information about how those cells would affect someone with schizophrenia than traditional testing methods.

In a news release Adam Margolin, from the Icahn Institute, said these findings could have wider implications:

“This study nicely illustrates the importance of using an integrative genomics approach for improving drug discovery and, ultimately, patient care. The results should be immediately applicable not only to drug discovery for schizophrenia but also more broadly to a wide range of diseases for which more biologically relevant screening models are long overdue.

Visual impairment and vision loss can have a profound impact on a person’s ability to live their life and complete their daily routine. According to the report for the 2016 National Health Interview Survey, 25.5 million Adult Americans 18 and older reported experiencing vision loss. Of these 25.5 million American adults, 15.3 million women and 10.1 million men report experiencing significant vision loss.

While some vision loss has been curbed with contact lenses, antibiotics or even surgery, other more serious conditions like macular degeneration, diabetic retinopathy, and inherited retinal degenerations, present greater challenges.

So what options are available?

Stem cell-based therapy.

Some say emerging stem cell technologies could hold the promise of autologous grafts to stabilize vision loss through cellular replacement or paracrine rescue effects. It is believed that since most of the diseases that lead to loss of vision do so as a result of abnormal vasculature and/or neuronal degeneration, the use of stem cells to stabilize or prevent visual loss may hold great promise. Our stem cell team will discuss these treatments, and what, if any approach may significantly address vision loss for stem cell researchers.

This event will feature Rosie Barrero, a patient advocate and clinical trial participant, Dennis Clegg,Co-Director, UCSB Center for Stem Cell Biology and Engineering and Henry Klassen, MD Ph.D, Director, UC Irvine Stem Cell & Retinal Regenerative Program.

Our Facebook Live event, “Ask the Stem Cell Team About Sickle Cell Disease” is– Thursday, November 1st – from noon till 1pm PST. You can join us by logging on to our Facebook.

Also, make sure to “like” our FaceBook page before the event to receive a notification when we’ve gone live for this and future events.

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

A recording of the session will be available in our FaceBook videos page shortly after the broadcast ends.

We hope to see you there.

Almost 15 years ago, California voters via approval of Proposition 71 authorized $3 billion to create the California Institute for Regenerative Medicine (CIRM). CIRM, otherwise known as California’s Stem Cell Agency, accelerates stem cell treatments for patients with unmet medical needs.

Credit: Starworks Network

Along with the fact that CIRM has pioneered the way for cutting edge science, we are also global innovators in empowering patient advocates to fully partner in biomedical research funding through a healthcare practice called “Coproduction” that is also being applied to biomedical research processes.

For those of you who are unfamiliar with the terminology, “coproduction” in healthcare in the US has also been called “patient-centered” care or “patient-centered medical home.”  As it is being applied to biomedical research, it is an approach in which researchers, practitioners and the public work together, sharing power and responsibility from the start to the end of the project, including the generation of knowledge. The global movement towards co-production gives patients and patient advocates formal roles as full partners so that research brings about outcomes that improve patients’ health more effectively and efficiently.  Both in healthcare and biomedical research, chronic and life threatening diseases and conditions offer the greatest need and produce the greatest benefits from robust coproduction.

Just last week one of our Board members, Jeff Sheehy, wrote a commentary which appeared in Nature, about coproduction. We spoke to him for a Q&A profile on the piece to give us his thoughts on this emerging trend.

Jeff Sheehy is a former San Francisco City and County Supervisor and a long-time HIV/AIDS activist and pioneer for LGBT equality who has dedicated his life to public and community service. He has served on CIRM’s Board since its inception in 2004.

AS: I know CIRM is unique, but what is one of the things that you see that CIRM does  or has done that’s unlike any other agency.

JS: One of the amazing things about the structure of CIRM is the way in which Proposition 71 actually gives formal power to patient advocates. CIRM is unique because patient advocate members of the Board are full participants in the Grants Working Group, CIRM’s peer review body, including writing reviews for late stage projects. That is one example, but when you look at CIRM, at every level patient advocates are critical to the functioning of the agency.  Advocates exert leadership in reviewing applications and approving funding them, participating in Clinical Advisory Panels to advise and monitor late stage projects, setting budgets, creating strategy, determining policies and selecting leadership of the institution. I believe this is unique – that CIRM treats patient advocates as full partners in the agency’s processes and ensures that participation with formal, statutory power.

AS: What’s one piece of advice that you would pass along to a patient advocate, or those who haven’t yet realized how much power they have to push things forward for certain disease indications?

JS: I would suggest that patient advocacy is beneficial in a number of ways. One is from a purely personal point of view. When one or one’s loved one is diagnosed with a chronic or life-threatening disease or condition, it is terrifying and the sense that one’s future is outside of one’s control is overwhelming.  For instance, when I was diagnosed with HIV in early 1997, even though life-saving combination therapy was just coming onto the scene, I did not have health insurance, did not know how to access care, and was not even completely sold on the efficacy of the new therapy.  I felt that I, like everyone diagnosed with HIV up to that point, had been given a death sentence. Joining my brothers and sisters in ACT-UP not only helped me understand and learn about HIV and the new therapy along with how to access care and the medications, but it also empowered and emboldened me to fight back not only for myself but for everyone impacted by HIV/AIDS. So, I took that first step of becoming an advocate for myself and my community.  Taking action, actively fighting for yourself, your loved ones, your community, learning about your disease and how to combat it—I think this has a psychological and I would argue even a physical benefit because you’re no longer passively accepting the cards you or your loved ones have been dealt.  In HIV, one of the most heavily stigmatized diseases, owning your diagnosis, working with others who have HIV, partnering with one’s caregivers, obliterates psychological barriers imposed by stigma and helps one achieve the self efficacy and resiliency necessary to survive and thrive.

Another way that patient advocates can bring great value to the struggle against chronic and life threatening diseases and conditions is to actively engage in the research process, to become a partner in the search for therapies and cures.  Multiple paths are available.  One can participate in a clinical trial, though it is extremely important to be aware of the risks and to recognize that the benefits of the research are unlikely to be realized by you.  In the first trial of a therapy for HIV in the early 1980s, every participant died, yet almost 15 years later we had developed combination therapy that, as an example of a “Lazarus effect,” literally brought AIDS patients out of their deathbeds. Research/medicine is able to make huge leaps forward due to the altruism of motivated trial participants.

Additionally, you can advocate for funding for research, which should also be linked to advocacy for policy changes that ensure access for everyone to new therapies and cures.  Proposition 71 was led by patient advocates, and CIRM, in its intellectual property policies, mandates access to newly discovered therapies and cures.  Also, if you look at the way CIRM operates, patient advocates take partnering to another level by active and equal participation in the functions of the agency.  Patient advocates not only need to be available to take part, but also we must strongly press the model of coproduction across the board so that other research entities recognize the immense value and benefit of engaging and creating partnerships with patients and patient advocates.

By: Shyam Patel

Over 1200 business and science leaders in regenerative medicine descended upon an uncharacteristically cloudy San Diego last week for the annual Cell and Gene Meeting on the Mesa. Reflecting the general growth and enthusiasm in the industry the meeting attracts so many attendees now that it is forced to move to a larger venue next year.

According to meeting organizer, the Alliance for Regenerative Medicine (ARM), there are currently 892 companies and 1000 clinical trials in regenerative medicine worldwide. To date, the regenerative medicine industry has raised a staggering $10.3B in financing, and IPOs and venture capital raises this year are already much higher than previous year totals. These, of course, are good problems to have.

The industry is still riding the euphoria generated by recent US market launches of the first gene modified cell therapies, Kymriah and Yescarta, and the first gene therapy, Luxturna. Both chimeric antigen receptor (CAR) T cell therapies and gene therapies were the stars of the meeting with almost all the panels featuring companies in these two areas. The successful launches of these products, along with the Food and Drug Administration’s commitment to RMAT (Regenerative Medicine Advanced Therapy, a new designation that can mean accelerated review for a treatment) and the aforementioned cash infusion, have reduced the industry’s anxiety around regulatory and financing risks.

Now the focus is on reimbursement and adoption strategies. The big challenge for the industry will be proving the value of these one-time potentially curative but expensive therapies to the healthcare system. These new ways to treat and cure diseases will need new ways to pay for them.

As in previous years CIRM-funded projects were very well represented at the meeting. Company presentations from CIRM grantees such as Caladrius, Capricor, Cellerant, Nohla Therapeutics, Regenerative Patch Technologies, Sangamo and ViaCyte showcased the breadth of regenerative medicine research in California. In addition, the science research talks by CIRM-funded investigators Helen Blau, Stephanie Cherqui, Matt Porteus and Mark Tuszynski, which ranged from muscle rejuvenation compounds to CRISPR’ing sickle cell disease, made it clear that the next wave of technologies is already on the horizon.

All of these presenters noted that CIRM funding was the crucial driver in progressing the projects out of the laboratory and into the clinic.

In the end, the 1500 partnering meetings that took place over two days were all focused on a singular goal: delivering revolutionary therapies as quickly as possible to patients in need.

By: Geoffrey Lomax Dr. PHD

In August, I had the pleasure of representing CIRM at California’s first conference dedicated entirely to training nurses and health professionals about cellular therapies. The City of Hope Alpha Stem Cell Clinic sponsored the program titled: Critical Role of Nursing Cellular Therapies. The Alpha Clinic at City of Hope has spent the past three years focusing on the role nurses play in the successful delivery new stem cell and regenerative medicine treatments to patients. They have published an article detailing this experience: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746156/pdf/SCT3-7-6.pdf

The event could not have come at a better time. More the 300,000 registered nurses are licensed in California – the state’s single largest health profession. There are over 875 regenerative medicine clinical trials in progress worldwide. These trials include gene and stem cell therapies. With an extensive network of world-class medical centers, California is ideally positioned as a leader in the regenerative medicine space that is witnessing billions of dollars in new investment annually.

The conference provided an opportunity for nurses and health professional to learn about the regenerative medicine clinical trials, including:

• Describing the nurse’s role in clinical trial research
• Understanding the ethical responsibilities of nurses in caring for patients undergoing cellular therapy
• Conveying the patient experience throughout the treatment process
• Describing procedures for administering cell therapies and monitoring for safety

A complete agenda may be found here: https://www.eventbrite.com/e/critical-role-of-nursing-in-cellular-therapies-tickets-45907582816#

Over 150 participants attended each day of the conference. The majority were registered or licensed nurses (86%) and other attendees included doctors, scientists, and students. The vast majority were from California, but participants traveled from New York, Florida, Arizona and Washington State to attend. Almost, all the session were graded as good to excellent by 90% of those responding to the program survey. One responded wrote:

On the whole, an incredibly professional, informative, and well-presented meeting.  Very impressive!

During breaks, I had the opportunity to meet participants. Many indicated that they are becoming aware of the growing field of regenerative medicine and wanted to transition their careers into this space.  They view this event as important for raising awareness of new opportunities for career development.

The CIRM Alpha Clinics Network is continuing with a series of educational webinars in the area of nursing and cell therapies. For more information contact:  jsprein@coh.org

TEDx talks are an excellent resource to learn about a myriad of subjects. They’re available on almost any subject and you can watch most of them in 18 minutes or less. This week instead of our traditional roundup, we are featuring a roundup of talks that caught our eye by speakers who are involved with CIRM.  

1. Stemming Vision Loss with Stem Cells by Dr. Dennis Clegg

Dr. Clegg earned his BS degree in biochemistry at UC Davis and his PhD in biochemistry at UC Berkeley, where he used emerging methods in recombinant DNA to study the sensory transduction systems of bacteria.

He is the co-founder of  Regenerative Patch Technologies (RPT), which is running a CIRM-funded clinical trial targeting age-related macular degeneration (AMD).

2. Childhood Poverty by Dr. Bert Lubin

Bertram Lubin, MD, is the first pediatrician to serve as president and chief executive officer in the 100-year history of Children’s Hospital & Research Center Oakland.

He is a former a CIRM Board Member. And his talk discusses childhood poverty and the shocking correlations between childhood poverty and disease.

3. Artificial Retinas for the Blind by Mark Humayun

Dr. Humayun is a CIRM funded professor of Ophthalmology, Biomedical Engineering, and Cell and Neurobiology at the Doheny Eye Institute, Keck School of Medicine at the University of Southern California. He has spent years developing this therapy and so it’s understandable that he might be a little nervous finally getting a chance to see if it works in people.

Representative, pseudo-colored image of how the researchers tracked cell differentiation (asterisks) and cell division (arrows). Image courtesy of Yale University.

Our body’s largest organ, the skin, regenerates itself on a weekly basis. To accomplish this goal, it maintains a self-renewing population of stem cells that can become the many different types of cells found within the skin. This self-renewal, however, must be tightly regulated because uncontrolled cell division can lead to disease like cancer. Investigators at Yale University have uncovered how the stem cell population as a whole controls this critical process. Their work was published in Cell Stem Cell last week.

One of the limitations to studying this population of self-renewing stem cells was the inability to simultaneously track a stem cell’s ability to undergo self-renewal or differentiation into a mature skin cell. Using an innovative form of spatio-temoral live imaging of individual stem cells in mice, the investigators found that death or differentiation of neighboring cells caused stem cells to undergo self-renewal. Interestingly, they found that this process was unidirectional, meaning that differentiation of a stem cell can lead to division, or self-renewal, of a neighboring cell, but self-renewal does not trigger differentiation in surrounding cells.

This finding is particularly interesting, because it indicates a shift in homeostatic mechanisms in developing skin versus adult skin. In an embryo, differentiation of stem cells regulates the differentiation of surrounding cells, whereas, in the adult epidermis, it appears that neighboring cells are responsible for promoting self-renewal of the stem cell population. The investigators confirmed their conclusions by experimentally forcing stem cells to differentiate and found that this induced neighboring cells to divide and undergo self-renewal.

These findings provide important insight into the basic biology behind stem cell renewal in one of our most dynamic organs, the skin.

Photo Credit: Mark Ellisman and Thomas Deerinck UC San Diego

Scientists at the University of California San Diego School of Medicine have created spinal cord neural stem cells (NSC) from human pluripotent stem cells (hPSCs), which could feasibly represent a source of transplantable cells for repairing spinal cord injuries.

The research, which was published in the journal Nature Methods, showed that the human spinal cord NSCs can be maintained over long periods in culture and, when transplanted into the injured spinal cords of rats, transformed into all the major neural cell types, the neurons or nerve cells responsible for sending signals in the brain and spinal cord, and the glia, which play a key supporting role to neurons. The grafts were particularly effective in creating axons, which carry signals from one neuron to another,  and promoting regeneration of the corticospinal tract, which controls our ability to move our arms and legs.

“In grafts, these cells could be found throughout the spinal cord, dorsal to ventral. They promoted regeneration after spinal cord injury in adult rats, including corticospinal axons, which are extremely important in human voluntary motor function. In rats, they supported functional recovery.”- Hiromi Kumamaru, M.D., Ph.D.

Cell-based therapies typically require a large number of specialized cells, which requires a series of steps changing embryonic stem cells into the desired cell . The UCSD team developed a faster process, generating large numbers of NSCs in the lab.

The researchers say spinal cord NSCs have the potential to be used for repairing spinal cord damage but to date, no one has managed to generate them in the lab.in vitro. Moreover, the ability to use such cells for spinal cord repair would only be feasible if they can generate all of the key cell types required inside the body, including the different types of neurons and supporting glial cells.

Initial experiments transplanting the cells into rats with spinal cord injuries showed that the grafted stem cell-derived human spinal cord NSCs survived and readily extended axons into the injured host spinal cord, even months after transplantation. Within three months 80% of the graft-derived cells expressed neuronal markers, and by six months post-transplantation, the populations of graft-derived cells expressed markers for other key support cells in the brain (called  oligodendrocytes and astrocytes) and neurons.

“These results indicate that H9-hESC-derived spinal cord NSCs can generate the three cardinal neural lineages in vivo (in the body),” the team wrote. More detailed analyses suggested that by six months post-transplantation, the spinal cord NSC grafts had transformed into a variety of neuronal subtypes that were helping to promote a robust spinal cord regeneration.

The team concluded that the ability of NSC to differentiate into multiple types of spinal cord neurons may be extremely valuable for testing potential therapies for other neural disorders such as ALS.

The researchers say their approach offers the potential for generating the large numbers of cells needed to treat spinal cord injury in a clinical setting, although they acknowledge that further studies will be needed to test the safety and effectiveness of the approach before testing it in people.