When Lili Yang was studying for her PhD she approached her mentor, the Nobel Laureate Dr. David Baltimore, and told him she was thinking about writing her thesis on a combination of gene therapy, immunotherapy and stem cell therapy. She says he looked at her and told her that all three of those approaches had a bad reputation because of so many past failures. He asked her, “Are you sure?” She was.
Fast forward 20 years and Dr. Yang and her team at UCLA have developed stem cell-engineered invariant Natural Killer T (iNKT) cells, a kind of specialized immune system cell, that has the ability to attack and kill a broad range of cancerous cells, while leaving the body’s healthy tissues unharmed.
Thanks to several CIRM grants, Dr. Yang has developed a platform that can use healthy donor blood stem cells to produce clinical scalable “off-the-shelf” iNKT cells. That has led to the creation of Appia Bio, a start-up company, and talks with the FDA about testing a series of iNKT cell products in clinical trials.
Besides developing cell products targeting the more established blood cancer disease indications, Dr. Yang is most excited about using the same platform to generate off-the-shelf iNKT cell products that could target solid tumor cancers that comprise over 90% of the total cancer cases, such as breast, ovarian, prostate, lung, liver, and colon cancers.
“I have this dream that cell therapy can become off-the-shelf, and how this would really help all cancer patients in need. The current cancer cell therapy requires treating patients one-by-one, resulting in a steep price that is hard to afford ($300,000-$500,000 per patient per treatment) and a complex therapy delivery logistics that is challenging to fulfill (coordination of hospitalization, blood collection, cell manufacturing and infusion for each patient). Not everyone lives near a hospital capable of handling such a personalized therapy or can afford such a steep price. If we can make this therapy with centralized manufacturing, pre-quality controlled and ready for wide use then we don’t need to worry about the gender or age or location of the patient. For off-the-shelf therapy, price is also expected to drop down significantly- this will eventually be ready for everyone everywhere.”
I’ve always been impressed by the willingness of individuals to step forward and volunteer for a clinical trial. Even more so when they are the first person ever to test a first-in-human therapy. They really are pioneers in helping advance a whole new approach to treating disease.
That’s certainly the case for the first individual treated in a CIRM-funded clinical trial to develop a functional cure for HIV/AIDS. Caring Cross announced recently that they have dosed the first patient in the trial testing their anti-HIV duoCAR-T cell therapy.
The trial is being led by UC San Francisco’s Dr. Steven Deeks and UC Davis’ Dr. Mehrdad Abedi. Their approach involves taking a patient’s own blood and extracting T cells, a type of immune cell. The T cells are then genetically modified to express two different chimeric antigen receptors (CAR), which enable the newly created duoCAR-T cells to recognize and destroy HIV infected cells. The modified T cells are then reintroduced back into the patient.
The goal of this one-time therapy is to act as a long-term control of HIV with patients no longer needing to take anti-HIV medications. If it is successful it would be, in effect, a form of functional HIV cure.
This first phase involves giving different patients different levels of the duoCAR-T therapy to determine the best dose, and to make sure it is safe and doesn’t cause any negative side effects.
This is obviously just the first step in a long process, but it’s an important first step and certainly one worth marking. As Dr. Deeks said in the news release, “We have reached an important milestone with the dosing of the first participant in the Phase 1/2a clinical trial evaluating a potentially groundbreaking anti-HIV duoCAR-T cell therapy. Our primary goal for this clinical trial is to establish the safety of this promising therapeutic approach.”
Dr. Abedi, echoed that saying. “The first participant was dosed with anti-HIV duoCAR-T cells at the UC Davis medical center in mid-August. There were no adverse events observed that were related to the product and the participant is doing fine.”
This approach carries a lot of significance not just for people with HIV in the US, but also globally. If successful it could help address the needs of people who are not able to access antiretroviral therapies or for whom those medications are no longer effective.
Our 2021-22 Annual Report is now online. It’s filled with information about the work we have done over the last year (we are on a fiscal calendar year from July 1 – June 30), the people who have helped us do that work, and some of the people who have benefited from that work. One of those is Dr. Alysson Muotri, a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego.
For Dr. Alysson Muotri, trying to unlock the secrets of the brain isn’t just a matter of scientific curiosity, it’s personal. He has a son with autism and Dr. Muotri is looking for ways to help him, and millions of others like him around the world.
He created the Tooth Fairy project where parents donated more than 3,000 baby teeth from children with autism and children who are developing normally. Dr. Muotri then turned cells from those teeth into neurons, the kind of brain cell affected by autism. He is using those cells to try and identify how the brain of a child with autism differs from a child who is developing normally.
“We’ve been using cells from this population to see what are the alterations (in the gene) and if we can revert them back to a normal state. If you know the gene that is affected, and autism has a strong genetic component, by genome sequencing you can actually find what are the genes that are affected and in some cases there are good candidates for gene therapy. So, you just put the gene back. And we can see that in the lab where we are correcting the gene that is mutated, the networks start to function in a way that is more neurotypical or normal. We see that as highly promising, there’s a huge potential here to help those individuals.”
He is also creating brain organoids, three-dimensional structures created from stem cells that mimic some of the actions and activities of the brain. Because these are made from human cells, not mice or other animals, they may be better at indicating if new therapies have any potential risks for people.
“We can test drugs in the brain organoids of the person and see if it works, see if there’s any toxicity before you actually give the drug to a person, and it will save us time and money and will increase our knowledge about the human brain.”
He says he still gets excited seeing how these cells work. “It’s amazing, it’s a miracle. Every time I see it, it’s like seeing dolphins in the sea because it’s so beautiful.”
Dr. Muotri is also a big proponent of diversity, equity and inclusion in scientific research. He says in the past it was very much a top-down model with scientists deciding what was important. He says we need to change that and give patients and communities a bigger role in shaping the direction of research.
“I think this is something we scientists have to learn, how to incorporate patients in our research. These communities are the ones we are studying, and we need to know what they want and not assume that what we want is what they want. They should be consulted on our grants, and they should participate in the design of our experiments. That is the future.”
Neurona Therapeutics is testing a new therapy for a drug-resistant form of epilepsy and has just released some encouraging early findings. The first patient treated went from having more than 30 seizures a month to just four seizures over a three-month period.
This clinical trial, funded by the California Institute for Regenerative Medicine (CIRM), is targeting mesial temporal lobe epilepsy (MTLE), one of the most common forms of epilepsy. Because the seizures caused by MTLE are frequent, they can be particularly debilitating and increase the risk of a decreased quality of life, depression, anxiety and memory impairment.
Neurona’s therapy, called NRTX-1001, consists of a specialized type of neuronal cell derived from embryonic stem cells. Neuronal cells are messenger cells that transmit information between different areas of the brain, and between the brain and the rest of the nervous system.
NRTX-1001 is injected into the brain in the area affected by the seizures where it releases neurotransmitters or chemical messengers that will block the signals in the brain causing the epileptic seizures.
The first patient treated had a nine-year history of epilepsy and, despite being on anti-epileptic medications, was experiencing dozens of seizures a month. Since the therapy he has had only four seizures in three months. The therapy hasn’t produced any serious side effects.
In a news release Dr. Cory Nicholas, Neurona’s President and CEO, said while this is only one patient, it’s good news.
“The reduced number of seizures reported by the first person to receive NRTX-1001 is very encouraging, and we remain cautiously optimistic that this reduction in seizure frequency will continue and extend to others entering this cell therapy trial. NRTX-1001 administration has been well tolerated thus far in the clinic, which is in line with the extensive preclinical safety data collected by the Neurona team. With recent clearance from the Data Safety Monitoring Board we are excited to continue patient enrollment. We are very grateful to these first participants, and thank the clinical teams for the careful execution of this pioneering study.”
CIRM has been a big supporter of this work from the early Discovery stage work to this clinical trial. That’s because when we find something promising, we want to do everything we can to help it live up to its promise.
The use of antiretroviral drugs has turned HIV/AIDS from a fatal disease to one that can, in many cases in the US, be controlled. But these drugs are not a cure. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) voted to approve investing $6.85 million in a therapy that aims to cure the disease.
This is the 82nd clinical trial funded by CIRM.
There are approximately 38 million people worldwide living with HIV/AIDS. And each year there are an estimated 1.5 million new cases. The vast majority of those living with HIV do not have access to the life-saving antiretroviral medications that can keep the virus under control. People who do have access to the medications face long-term complications from them including heart disease, bone, liver and kidney problems, and changes in metabolism.
The antiretroviral medications are effective at reducing the viral load in people with HIV, but they don’t eliminate it. That’s because the virus that causes AIDS can integrate its DNA into long-living cells in the body and remain dormant. When people stop taking their medications the virus is able to rekindle and spread throughout the body.
Dr. William Kennedy and the team at Excision Bio Therapeutics have developed a therapeutic candidate called EBT-101. This is the first clinical study using the CRISPR-based platform for genome editing and excision of the latent form of HIV-1, the most common form of the virus that causes AIDS in the US and Europe. The goal is to eliminate or sufficiently reduce the hidden reservoirs of virus in the body to the point where the individual is effectively cured.
“To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative,” says Dr. Maria Millan, President and CEO of CIRM. “In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.”
In a news release announcing they had dosed the first patient, Daniel Dornbusch, CEO of Excision, called it a landmark moment. “It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient and is expected to enable the first ever clinical assessment of a multiplexed, in vivo gene editing approach. We were able to reach this watershed moment thanks to years of innovative work by leading scientists and physicians, to whom we are immensely grateful. With this achievement, Excision has taken a major step forward in developing a one-time treatment that could transform the HIV pandemic by freeing affected people from life-long disease management and the stigma of disease.”
The Excision Bio Therapeutics team also scored high on their plan for Diversity, Equity and Inclusion. Reviewers praised them for adding on a partnering organization to provide commitments to serve underserved populations, and to engaging a community advisory board to help guide their patient recruitment.
For children born with severe combined immunodeficiency (SCID) life can be very challenging. SCID means they have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life.
There are stem cell/gene therapies funded by the California Institute for Regenerative Medicine (CIRM), such as ones at UCLA and UCSF/St. Judes, but an alternative method of treating, and even curing the condition, is a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s blood supply with one that is free of the SCID mutation, which helps restore their immune system.
However, current HCT methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
To change that, Dr. Judy Shizuru at Stanford University, with CIRM funding, developed an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells, creating the room needed to transplant new, healthy cells. The goal was to make stem cell transplants safer and more effective for the treatment of many life-threatening blood disorders.
That approach, JSP191, is now being championed by Jasper Therapeutics and they just got some very good news from the Food and Drug Administration (FDA). The FDA has granted JSP191 Fast Track Designation, which can speed up the review of therapies designed to treat serious conditions and fill unmet medical needs.
In a news release, Ronald Martell, President and CEO of Jasper Therapeutics, said this is good news for the company and patients: “This new Fast Track designation recognizes the potential role of JSP191 in improving clinical outcomes for these patients and will allow us to more closely work with the FDA in the upcoming months to determine a path toward a Biologics License Application (BLA) submission.”
Getting a BLA means Jasper will be able to market the antibody in the US and make it available to all those who need it.
This is the third boost from the FDA for Jasper. Previously the agency granted JSP191 both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.
September is National Sickle Cell Awareness Month, a time to refocus our efforts to find new treatments, even a cure, for people with sickle cell disease. Until we get those, CIRM remains committed to doing everything we can to reduce the stigma and bias that surrounds it.
Sickle cell disease (SCD) is a rare, inherited blood disorder in which normally smooth and round red blood cells may become sickle-shaped and harden. These blood cells can clump together and clog up arteries, causing severe and unpredictable bouts of pain, organ damage, vision loss and blindness, strokes and premature death.
There is a cure, a bone marrow transplant from someone who is both a perfect match and doesn’t carry the SCD trait. However, few patients are able to find that perfect match and even if they do the procedure carries risks.
The GRASP Trial is a Phase 2 trial that will take place at various locations throughout the country. It’s a collaboration between the NHLBI and CIRM. Researchers are testing whether a gene therapy approach can improve or eliminate sickle cell pain episodes.
Shortly after being born, babies stop producing blood containing oxygen-rich fetal hemoglobin and instead produce blood with the adult hemoglobin protein. For children with sickle cell disease, the transition from the fetal to the adult form of hemoglobin marks the onset of anemia and the painful symptoms of the disorder.
Scientists previously discovered that the BCL11A gene helps to control fetal hemoglobin and that decreasing the expression of this gene can increase the amount of fetal hemoglobin while at the same time reducing the amount of sickle hemoglobin in blood. This could result in boosting the production of normal shaped red blood cells with a goal of curing or reducing the severity of sickle cell disease.
The approach used in this trial is similar to a bone marrow transplant, but instead of using donor stem cells, this uses the patient’s own blood stem cells with new genetic information that instructs red blood cells to silence the expression of the BCL11A gene. This approach is still being studied to make sure that it is safe and effective, but it potentially has the advantage of eliminating some of the risks of other therapies.
In this trial, patients will have to spend some time in an inpatient unit as they undergo chemotherapy to kill some bone marrow blood stem cells and create room for the new, gene-modified cells to take root.
The trial is based on a successful pilot/phase 1 study which showed it to be both safe and effective in the initial 10 patients enrolled in the trial.
For more information about the trial, including inclusion/exclusion criteria and trial locations, please visit the CureSCi GRASP trial page.
Nancy Rene, a sickle cell disease patient advocate, says while clinical trials like this are obviously important, there’s another aspect of the treatment of people with the disease that is still too often overlooked.
“As much as I applaud CIRM for the work they are doing to find a therapy or cure for Sickle Cell, I am often dismayed by the huge gulf between research protocols and general medical practice. For every story I hear about promising research, there is often another sad tale about a sickle cell patient receiving inadequate care. This shouldn’t be an either/or proposition. Let’s continue to support ground-breaking research while we expand education and training for medical professionals in evidenced based treatment. I look forward to the day when sickle cell patients receive the kind of treatment they need to lead healthy, pain-free lives.”
Growing up Veronica McDougall thought everyone saw the world the way she did; blurry, slightly out-of-focus and with tunnel vision. As she got older her sight got worse and even the strongest prescription glasses didn’t help. When she was 15 her brother tried teaching her to drive. One night she got into the driver’s seat to practice and told him she couldn’t see anything. Everything was just black. After that she stopped driving.
Veronica says high school was really hard for her, but she managed to graduate and go to community college. As her vision deteriorated, she found it was increasingly hard to read the course work and impossible to see the assignments on the blackboard. Veronica says she was lucky to have some really supportive teachers — including the now First Lady Jill Biden — but eventually she had to drop out.
Getting a diagnosis
When she was 24, she went to see a specialist who told her she had retinitis pigmentosa, a rare degenerative condition that would eventually leave her legally blind. She says it felt like a death sentence. “All of my dreams of becoming a nurse, of getting married, of having children, of traveling – it all just shattered in that moment.”
Veronica says she went from being a happy, positive person to an angry depressed one. She woke up each morning terrified, wondering, “Is this the day I go blind?”
Then her mother learned about a CIRM-funded clinical trial with a company called jCyte. Veronica applied to be part of it, was accepted and was given an injection of stem cells in her left eye. She says over the course of a few weeks, her vision steadily improved.
“About a month after treatment, I was riding in the car with my mom and suddenly, I realized I could see her out of the corner of my eye while looking straight ahead. That had never, ever happened to me before. Because, I had been losing my peripheral vision at a young age without realizing that until up to that point, I had never had that experience.”
A second chance at life
She went back to college, threw herself into her studies, started hiking and being more active. She says it was as if she was reborn. But in her senior year, just as she was getting close to finishing her degree, her vision began to deteriorate again. Fortunately, she was able to take part in a second clinical trial, and this time her vision came back stronger than ever.
“I’m so grateful to the researchers who gave me my sight back with the treatment they have worked their entire lives to develop. I am forever grateful for the two opportunities to even receive these two injections and to be a part of an amazing experience to see again. I feel so blessed! Thank you for giving me my life back.”
And in getting her life back, Veronica had a chance to give life. When she was at college she met and starting dating Robert, the man who was to become her partner. They now have a little boy, Elliott.
As for the future, Veronica hopes to get a second stem cell therapy to improve her vision even further. Veronica’s two treatments were in her left eye. She is hoping that the Food and Drug Administration will one day soon approve jCyte’s therapy, so that she can get the treatment in her right eye. Then, she says, she’ll be able to see the world as the rest of us can.
So, I reached out to Jackie and asked her some questions about her work and career. She generously put aside keeping the nation healthy to answer them. Enjoy.
What made you decide to move from research into government.
I think if you asked my high school government teacher (shout out to Mr. Bell!), he would be the least surprised person that I have ended up where I am currently. I was always interested in topics and activities beyond science, but at a certain point you have to choose a path. When it came time to deciding my undergraduate major, I figured that if I pursued my interest in biology it would still keep my options open to do something different in my career, but if I chose to be a French major, or Political Science major, or English major – I might close the door in my ability to pursue scientific research. When I got to graduate school, I saw the impact of government (both state and federal) decisions on work in the lab. This takes the form of where funding goes, but also in the rules you have to follow while doing research. Though I liked the pursuit of new knowledge and being the one designing and performing experiments, I was interested in understanding more about how those government decisions are made upstream of the lab bench.
What’s the most surprising thing you have learned in your time at the White House Office of Science and Technology Policy (OSTP).
Maybe not “surprising” but the thing that may not be obvious to outsiders: OSTP’s budget is tiny compared to other Executive Branch agencies (like where I came from previously at NIH). The work we accomplish in this office is solely by forming partnerships and collaborations with others across the government. We are not typically the rowers of the boat, but we can be the steerer or navigator. (Is the term coxswain? I have never been on a crew team obviously.)
Was it hard making the transition from research to advocacy and now policy?
Honestly I feel like my training in research set me up well for the jobs I’ve had in policy. There is often not someone telling you exactly how to do something – you have to do the work yourself to search the literature, talk to other people, find collaborators, and keep at it. And the skills that you hone in research – from keeping an organized lab notebook the whole way through to writing scientific papers – are some of the same skills you need in government.
At a time when so many people seem so skeptical of science how do you get your message out.
We have to meet people where they are. As a government official, I have great respect for messages that come from experts within the government – but that is not the only way the message should be getting out. Scientists and other experts within communities should also be spokespeople for science. I would urge scientists at every level – whether you are a citizen scientist, a medical doctor, a PhD student, or some other kind of expert – to engage with their communities and put the work in to understand how to effectively communicate at levels beyond just speaking to your colleagues.
One of the issues that so many of us, including here at CIRM, are working on is improving our performance in diversity, equity and inclusion. How big an issue is that for you and your colleagues at OSTP and what are you doing to try and address it.
The mission of our office is to “maximize the benefits of science and technology to advance health, prosperity, security, environmental quality, and justice for all Americans.” Those final two words are key: “all Americans.” It is the policy of this Office and our Administration that it is not okay for the benefits of science & technology to only reach a select few – who can afford it or who live in a certain zip code or who know the right people.
This takes different forms depending on what kind of S&T work we are talking about, but I will give you an example from my own work. I have been leading an effort that aims to explore and act upon how digital health care delivery technologies can be used to increase access to healthcare in community-based health settings. We know that these cutting edge technologies are most likely to get to people who, for example, get their care at academic medical centers, or who have primo health insurance plans, or who are already tech savvy. We feel that as these technologies continue to grow within the healthcare system, that it is an imperative to ensure that they are accessible to practitioners and patients at community health centers, or to people who may not be tech geeks, or that they can be interoperable with the systems used by community health workers.
During a time of Covid and now Monkeypox, what’s it like to have a front row seat and watch how government responds to public health emergencies.
My colleagues who work on outbreaks and pandemic responses are some of the most dedicated public servants I know. They will be the first to admit that we are continually learning and integrating new tools and technologies into our toolbox, and that is a constant effort. Emergent issues like outbreaks force decisions when there may not be a lot of information – that is a hard job.
I’ve always felt that DC would be a fun place to live and work (except during the height of summer!) what do you most like about it.
DC is a city full of people who care deeply (almost to a pathological extent) about the work they do and how to make the world a better place. There’s also incredible diversity here – which means a variety of viewpoints, languages, and food! I love that.
Jackie is not just a good writer. She’s also a great speaker. Here’s a clip of her responding to our Elevator Challenge many years ago, when she was still a fledgling researcher. Her explanation of what she does, is a master class in turning a complex subject into something easy to understand.
Jill Helms is not your average Stanford University faculty member. Yes, she is a professor in the Department of Surgery. Yes, she has published lots of scientific studies. Yes, she is a stem cell scientist (funded by CIRM). And yes, she is playing a leading role in Ankasa Regenerative Therapeutics, a company focused on tissue repair and regeneration. But she is so much more than all that.
She is a brilliant public speaker, a fashionista, and has ridden her horse to work (well, Stanford is referred to as The Farm, so why not!) and she lives on a farm of her own called “Follow Your Bliss.” The name comes from philosopher Joseph Campbell who wrote, “If you follow your bliss, you put yourself on a kind of path that has been there all the while, waiting for you. And the life you ought to be living is the one you are living.”
Dr. Helms says that pretty much sums up her life. She says she feels enormously blessed.
Well, we felt enormously blessed when she agreed to sit down with us and chat about her work, her life and her love of fashion for the California Institute for Regenerative Medicine podcast, Talking ‘Bout (re)Generation.