Canavan disease is a fatal neurological disorder, the most prevalent form of which begins in infancy. It is caused by mutation of the ASPA gene, resulting in the deterioration of white matter (myelin) in the brain and preventing the proper transmission of nerve signals. The mutated ASPA gene causes the buildup of an amino acid called NAA and is typically found in neurons in the brain. As a result of the NAA buildup, Canavan disease causes symptoms such as impaired motor function, mental retardation, and early death. Currently, there is no cure or standard of treatment for this condition.
Fortunately, CIRM-funded research conducted at City of Hope by Yanhong Shi, Ph.D. is developing a stem cell-based treatment for Canavan disease. The research is part of CIRM’s Translational Stage Research Program, which promotes the activities necessary for advancement to clinical study of a potential therapy.
The results from the study are promising, with the therapy improving motor function, reducing degeneration of various brain regions, and expanding lifespan in a Canavan disease mouse model.
For this study, induced pluripotent stem cells (iPSCs), which can turn into virtually any type of cells, were created from skin cells of Canavan disease patients. The newly created iPSCs were then used to create neural progenitor cells (NPCs), which have the ability to turn into various types of neural cells in the central nervous system. A functional version of the ASPA gene was then introduced into the NPCs. These newly created NPCs were then transplanted inside the brains of Canavan disease mice.
The study also used iPSCs engineered to have a functional version of the ASPA gene. The genetically modified iPSCs were then used to create oligodendrocyte progenitor cells (OPCs), which have the ability to turn into myelin. The OPCs were also transplanted inside the brains of mice.
The rationale for evaluating both NPCs and OPCs was that NPCs typically stayed at the site of injection while OPCs tend to migrate, which might have been important in terms of the effectiveness of the therapy. However, the results of the study show that both NPCs and OPCs were effective, with both being able to reduce levels of NAA, presumably because NAA can move to where the ASPA enzyme is although NPCs do not migrate. This resulted in improved motor function, recovery of myelin, and reduction of brain degeneration, in both the NPC and OPC-transplanted Canavan disease mice.
“Thanks to funding from CIRM and the hard work of my team here at City of Hope and collaborators at Center for Biomedicine and Genetics, Department of Molecular Imaging and Therapy, and Diabetes and Metabolism Institute at City of Hope, as well as collaborators from the University of Texas Medical Branch at Galveston, University of Rochester Medical Center, and Aarhus University, we were able to carry out this study which has demonstrated promising results,” said Dr. Shi. “I hope that these findings can one day bring about an effective therapy for Canavan disease patients, who currently have no treatment options.”
Dr. Shi and her team will build on this research by starting IND-enabling studies using their NPC therapy soon. This is the final step in securing approval from the Food and Drug Administration (FDA) in order to test the therapy in patients.
Last year, CIRM awarded $5.53 million to Rosa Bacchetta, M.D. at Stanford University to complete the work necessary to conduct a clinical trial for IPEX syndrome. This is a rare disease caused by mutations in the FOXP3 gene, which leaves people with the condition vulnerable to immune system attacks on their organs and tissues. These attacks can be devastating, even fatal.
Flash forward to the present day and the CIRM-funded treatment that Dr. Bacchetta has been working on has received both an orphan drug and a rare pediatric disease designation from the Food and Drug Administration (FDA).
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.
Under the FDA’s rare pediatric disease designation program, the FDA may grant priority review to Dr. Bacchetta if this treatment eventually receives FDA approval. The FDA defines a rare pediatric disease as a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and affects fewer than 200,000 people in the U.S.
“The designations granted by the FDA are a strong encouragement for our team to meet the goal of submitting the IND in 2021 and start the clinical trial for IPEX patients who are so much looking forward to new therapeutic options.” said Dr. Bacchetta.
But this begs the question, what exactly is IPEX syndrome? What is the approach that Dr. Bacchetta is working on? For those of you interested in the deeper scientific dive, we will elaborate on this complex disease and promising approach.
IPEX syndrome is a rare disease that primarily affects males and is caused by a genetic mutation that leads to lack of function of specialized immune cells called regulatory T cells (Tregs).
Without functional Tregs, a patient’s own immune cells attack the body’s own tissues and organs, a phenomenon known as autoimmunity. This affects many different areas such as the intestines, skin, and hormone-producing glands and can be fatal in early childhood.
Current treatment options include a bone marrow transplant and immune suppressing drugs. However, immune suppression is only partially effective and can cause severe side effects while bone marrow transplants are limited due to lack of matching donors.
Dr. Rosa Bacchetta and her team at Stanford will take a patient’s own blood in order to obtain CD4+ T cells. Then, using gene therapy, they will insert a normal version of the mutated gene into the CD4+ T cells, allowing them to function like normal Treg cells. These Treg-like cells would then be reintroduced back into the patient, hopefully creating an IPEX-free blood supply and resolving the autoimmunity.
Furthermore, if successful, this treatment could be adapted for treatment of other, more common, autoimmune conditions where Treg cells are the underlying problem.
The same day that CIRM approved funding for this approach, Taylor Lookofsky, a young man with IPEX syndrome, talked about the impact the condition has had on his life.
It’s a powerful reminder that syndromes like this, because they affect a small number of people, are often overlooked and have few resources devoted to finding new treatments and cures. After hearing Taylor’s story, you come to appreciate his courage and determination, and why the funding CIRM provides is so important in helping researchers like Dr. Bacchetta find therapies to help people like Taylor.
An antibody therapeutic, magrolimab, being tested for myelodysplastic syndrome (MDS), a group of cancers in which the bone marrow does not produce enough healthy blood cells , was granted breakthrough therapy designation with the Food and Drug Administration (FDA).
Breakthrough therapy designations from the FDA are intended to help expedite the development of new treatments. They require preliminary clinical evidence that demonstrates that the treatment may have substantial improvement in comparison to therapy options currently available. CIRM funded a Phase 1b trial in MDS and acute myeloid leukemia (AML), another type of blood cancer, that provided the data on which the breakthrough therapy designation is based.
Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.
Magrolimab was initially developed by a team led by Irv Weissman, M.D. at Stanford University with the support of CIRM awards. This led to the formation of Forty Seven, Inc., which was subsequently acquired by Gilead Sciences in April 2020 for $4.9 billion (learn more about other highlighted partnership events on CIRM’s Industry Alliance Program website by clicking here).
In CIRM’s 2019-2020 18-Month Report, Mark Chao, M.D., Ph.D., who co-founded Forty Seven, Inc. and currently serves as the VP of oncology clinical research at Gilead Sciences, credits CIRM with helping progress this treatment.
“CIRM’s support has been instrumental to our ability to rapidly progress Forty Seven’s CD47 antibody targeting approach.”
Magrolimab is currently being studied as a combination therapy with azacitidine, a chemotherapy drug, in a Phase 3 clinical trial in previously untreated higher risk MDS. This is one of the last steps before seeking FDA approval for widespread commercial use.
In a press release, Merdad Parsey, M.D., Ph.D., Chief Medical Officer at Gilead Sciences discusses the significance of the designation from the FDA and the importance of the treatment.
“The Breakthrough Therapy designation recognizes the potential for magrolimab to help address a significant unmet medical need for people with MDS and underscores the transformative potential of Gilead’s immuno-oncology therapies in development.”
This week saw the launch of the 45th startup company enabled by CIRM funding of translational research at California academic institutions. Graphite Bio officially launched with the help of $45M in funding led by bay area venture firms Versant Ventures and Samsara BioCapital to spinout a novel CRISPR gene editing platform from Stanford University to treat severe diseases. Graphite Bio’s lead candidate is for sickle cell disease and it harnesses CRISPR gene correction technology to correct the single DNA mutation in sickle cell disease and to restore normal hemoglobin expression in the red blood cells of sickle cell patients (Learn more about CRISPR from a previous blog post linked here).
Matt Porteus, M.D., Ph.D and Maria Grazia Roncarolo, M.D., both from Stanford University, are the company’s scientific founders. Dr. Porteus, Dr. Roncarolo, and the Stanford team are currently supported by a CIRM late stage preclinical grant to complete the final preclinical studies and to file an Investigational New Drug application with the FDA, which will enable Graphite Bio to commence clinical studies of the CRISPR sickle cell disease gene therapy candidate in sickle cell patients in 2021.
Josh Lehrer, M.D., was appointed CEO of Graphite Bio and elaborated on the company’s gene editing approach in a news release.
“Our flexible, site-specific approach is extremely powerful and could be used to definitively correct the underlying causes of many severe genetic diseases, and also is applicable to broader disease areas. With backing from Versant and Samsara, we look forward to progressing our novel medicines into the clinic for patients with high unmet needs.”
In a press release, Dr. Porteus take a retrospective look on his preclinical research and its progress towards a clinical trial.
“It is gratifying to see our work on new gene editing approaches being translated into novel therapies. I’m very excited to be working with Versant again on a start-up and I look forward to collaborating with Samsara and the Graphite Bio team to bring a new generation of genetic treatments to patients.”
CIRM’s funding of late stage preclinical projects such this one is critical to its funding model, which de-risks the discovery, translational development and clinical proof of concept of innovative stem cell-based treatments until they can attract industry partnerships. You can learn more about CIRM-enabled spinout companies and CIRM’s broader effort to facilitate industry partnering for its portfolio projects on CIRM’s Industry Alliance Program website.
You can contact CIRM’s Director of Business Development at the email below to learn more about the Industry Alliance Program.
Here at CIRM we only fund clinical trials that meet the rigorous standards outlined by the Food and Drug Administration (FDA). These requirements are not only necessary to properly evaluate how effective a potential treatment may be, but they are also important in fulfilling the Hippocratic Oath to “first, do no harm”.
The journey from the bench to the bedside for a potential treatment is one that is long, arduous, and often filled with setbacks. Unfortunately, there are those affected with various diseases that do not have the luxury of time. People who have suffered brain or spinal cord damage, or have been diagnosed with neurological disease, are often frustrated by the lack of treatments available to help them. That frustration can make them susceptible to the false promises made by predatory clinics, which operate outside of FDA oversight and offer “stem cell” treatments that are unproven and cost upwards of $50,000. In the midst of a global pandemic, some of these predatory clinics are even promoting false cures for COVID-19.
In an effort to better understand how often people gravitate to these predatory clinics, a phenomenon known as stem cell tourism, Dr. Jaime Imitola and a team of researchers at UConn Health conducted a nationwide survey of academic neurologists’ experiences in stem cell tourism complications. The study also evaluated the level of physician preparation to counsel and educate patients. These neurologists will typically have patients come to them asking for permission, a kind of “clearance” in their eyes, to get these unapproved stem cell treatments.
The results of the survey were very revealing. Of the neurologists who responded to the survey, one in four had a patient with complications related to stem cell therapy, which includes infections, strokes, spinal tumors, seizures, and even death. Additionally, 73% of neurologists responding to the survey said they felt that having more educational tools to discuss the issue with patients would be helpful.
In a press release, Dr. Imitola elaborated on the importance of this study.
“It is really shocking that only 28% of board-certified neurologists feel completely prepared to discuss this important issue with their patients…The ultimate goal of this research is to be able to determine the extent of the complications and the readiness of neurologists to counsel patients. All of us are interested in bringing real stem cells to the clinic, but this process is arduous and requires a great level of rigor and reproducibility.”
Dr. Imitola and his team also plan on starting a national patient registry, where physicians can report complications from stem cell tourism procedures. This would not only provide a better sense of the problem at hand, it would gather data that physicians could use to better educate patients.
The full results to this study were published in Annals of Neurology.
CIRM has produced a short video and other easy to digest information on questions people should ask before signing up for any clinical trial. You can find those resources here.
CIRM has also published findings in Stem Cells Translational Medicine that discuss the three R’s–regulated, reliable, and reputable–and how these can help protect patients with uniform standards for stem cell treatments .
This past Friday, the governing Board of the California Institute for Regenerative Medicine (CIRM) expanded the eligibility criteria for COVID-19 related projects to develop new treatments against the virus. Just two weeks ago, the Board approved $5 million in emergency funding for COVID-19 research.
One major addition is allowing research related to convalescent plasma to be eligible for CIRM COVID-19 emergency funding. Plasma is a component of blood that carries cells and antibodies. Blood plasma from patients that have recovered from COVID-19, referred to as convalescent plasma, contains antibodies against the virus and could be used as a potential treatment for COVID-19 patients.
In addition to this, potential clinical studies of convalescent plasma are now approved for use by the U.S. Food and Drug Administration (FDA) single-patient emergency Investigational New Drug (eIND) pathway as opposed to only a traditional IND. Before treatments can be tested in humans, a traditional IND needs to be filed. In an emergency situation such as the coronavirus pandemic, an eIND can be filed to begin testing the treatment faster.
In order to address the disproportionate impact of COVID-19 on underserved communities, priority will be given to projects that directly address these disparities.
Lastly, potential clinical programs for COVID-19 are now approved to start incurring allowable project costs, at risk, from the date of the application submission deadline. This would give researchers the opportunity to start their projects earlier and cover project costs retroactively if they are approved for funding.
“The intent behind this amendment is to be responsive to this COVID-19 crisis by leveraging CIRM’s funding programs, processes, and infrastructure within the scientific ecosystem that it has supported to date,” said Maria T. Millan, M.D., President and CEO of CIRM. “By providing an opportunity for the medical and scientific community to gather important data while using convalescent plasma treatment protocols on an emergency basis, CIRM is joining the global effort to expedite treatments to patients in need in the midst of this global pandemic.”
CIRM has established an open call for proposals and will accept applications on a bi-monthly basis.
Please refer to the following Program Announcement for more details:
Go to the Grants Management Portal (https://grants.cirm.ca.gov) and log in with your existing CIRM Username and Password. If you do not have a Username, Click on the “New User” link and follow the instructions to create a CIRM Username and password.
After logging in, click on the Menu tab. Select the tab labeled “Open Programs“. Under the section labeled “RFAs and Programs Open for Applications“, click on the “Start a Grant Application” link for your selected program.
Complete each section of the Application by clicking on the appropriate link and following the posted instructions. Proposal templates can be located and submitted under the “Uploads” section.
To submit your Application, click on the “Done with Application” button. The “Done with Application” button will be enabled when all of the mandatory sections have been completed. Please note that once this has been selected, you will no longer be able to make changes to your Application.
To confirm submission of your Application, select the tab labeled “Your Applications” and check the table under the section labeled “Your Submitted Applications“. You will see your Application number and project title listed once the submission process has been completed.
As the coronavirus pandemic continues to spread, one of the few bright spots is how many researchers are stepping up and trying to find new ways to tackle it, to treat it and hopefully even cure it. Unfortunately, there are also those who are simply trying to cash in on it.
In the last few years the number of predatory clinics offering so-called “stem cell therapies” for everything from Alzheimer’s and multiple sclerosis to autism and arthritis has exploded in the US. The products they offer have not undergone a clinical trial to show that they work; they haven’t been approved by the US Food and Drug Administration (FDA); they don’t have any evidence they are even safe. But that doesn’t stop them marketing these claims and it isn’t stopping some of them from now trying to cash in on the fears created by the coronavirus.
One company is hawking what it calls a rapid COVID-19 test, one that can determine if you have the virus in under ten minutes (many current tests take days to produce a result). All it takes is a few drops of blood and, from the comfort of your own home, you get to find out if you are positive for COVID-19. And best of all, it claims it is 99 percent accurate.
What could be the problem with that? A lot as it turns out.
If you go to the bottom of the page on the website marketing the test it basically says “this does not work and we’re not making any claims or are in any way responsible for any results it produces.” So much for 99 percent accurate.
It’s not the only example of this kind of shameless attempt to cash in on COVID-19. So it’s appropriate that this week the Alliance for Regenerative Medicine (ARM), issued a statement strongly condemning these attempts and the clinics behind them.
ARM warns about the growing number of “stem cell clinics” (that) are taking advantage of the “hype” around stem cells – and, in certain cases, the current concern about COVID-19 – and avoiding regulation by falsely marketing illegal and potentially harmful products to patients seeking cures.”
These so called “therapies” or tests do more than just take money – in some cases tens of thousands of dollars – from individuals: “Public health is at risk when unscrupulous providers offer stem cell products that are unapproved, unproven and fail to adhere to established rules for good manufacturing practices. Many of these providers put patients at risk by falsely marketing the benefits of treatments, and often promoting the stem cells for conditions that are outside of their area of medical expertise.”
It’s sad that even in times when so many people are working hard to find treatments for the virus, and many are risking their lives caring for those who have the virus, that there are unscrupulous people trying to make money out of it. All we can do is be mindful, be careful and be suspicious of anything that sounds too good to be true.
There are no miracle cures. No miracle treatments. No rapid blood tests you can order in the mail. Be aware. And most importantly of all, be safe.
The CIRM Board recently held a meeting to approve $5 million in emergency funding for rapid research into potential treatments for COVID-19.
The field of stem cell research and regenerative medicine has exploded in the last few years with new approaches to treat a wide array of diseases. Although these therapies are quite promising, they face many challenges in trying to bring them from the laboratory and into patients. But why is this? What can we do to ensure that these approaches are able to cross the finish line?
A new article published in Cell Stem Cell titled Translating Science into the Clinic: The Role of Funding Agencies takes a deeper dive into these questions and how agencies like CIRM play an active role in helping advance the science. The article was written by Dr. Maria T. Millan, President & CEO of CIRM, and Dr. Gil Sambrano, Vice President of Portfolio Development and Review at CIRM.
Although funding plays an essential role in accelerating science, it is not by itself sufficient. The article describes how CIRM has established internal processes and procedures that aim to help accelerate projects in the race to the finish line. We are going to highlight a few of these in this post, but you can read about them in full by clicking on the article link here.
One example of accelerating the most promising projects was making sure that they make important steps along the way. For potential translational awards, which “translate” basic research into clinical trials, this means having existing data to support a therapeutic approach. For pre-clinical and clinical awards, it means meeting with the Food and Drug Administration (FDA) and having an active investigational new drug (IND) approved or pre-IND, important steps that need to be taken before these treatments can be tested in humans. Both of these measures are meant to ensure that the award is successful and progress quickly.
Another important example is not just giving these projects the funding in its entirety upfront, rather, tying it to milestones that guide a project to successful completion. Through this process, projects funded by CIRM become focused on achieving clear measurable objectives, and activities that detract from those goals are not supported.
Aside from requirements and milestones tied to funding, there are other ways that CIRM helps bolster its projects.
One of these is an outreach project CIRM has implemented that identifies investigators and projects with the potential to enhance already existing projects. This increases the number of people applying to CIRM projects as well as the quality of the applications.
Another example is CIRM’s Industry Alliance Program, which facilitates partnerships between promising CIRM-funded projects and companies capable of bringing an approved therapy to market. The ultimate goal is to have therapies become available to patients, which is generally made possible through commercialization of a therapeutic product by a pharmaceutical or biotechnology company.
CIRM has also established advisory panels for its clinical and translational projects, referred to as CAPs and TAPs. They are composed of external scientific advisors with expertise that complements the project team, patient advocate advisors, and CIRM Science Officers. The advisory panel provides guidance and brings together all available resources to maximize the likelihood of achieving the project objective on an accelerated timeline.
Lastly, and most importantly, CIRM has included patient advocates and patient voices in the process to help keep the focus on patient needs. In order to accelerate therapies to the clinic, funders and scientists need input on what ultimately matters to patients. Investing effort and money on potential therapies that will have little value to patients is a delay on work that really matters. Even if there is not a cure for some of these diseases, making a significant improvement in quality of life could make a big difference to patients. There is no substitute to hearing directly from patients to understand their needs and to assess the balance of risk versus benefit. As much as science drives the process of bringing these therapies to light, patients ultimately determine its relevance.
We are at a turning point in regenerative medicine as the first wave of treatments have obtained FDA approval. But at the same time as we see the advance of scientifically rigorous research and regulated products we are also witnessing the continued proliferation of “unproven treatments.” This dueling environment can be overwhelming and distracting to individuals and families trying to manage life-threatening diseases.
How does a patient navigate this environment and get trusted and reliable information to help sort through their options?
CIRM teamed up with the CURA Foundation to organize a roundtable discussion intended to answer this question. The conversation included thought leaders involved in patient advocacy, therapy research and development, public policy and research funding. The roundtable was divided into three segments designed to discuss:
Examples of state-of-the-art patient navigation systems,
Policy, research and infrastructure needs required to expand navigation systems, and
Communication needs for engaging patients and the broader community.
Examples of Navigation Systems:
This session was framed around the observation that patients often do not get the best medicines or treatments available for their condition. For example, in the area of cancer care there is evidence that the top 25% of cancers are not being treated optimally. Historic barriers to optimal treatment include cost pressures that may block access to treatments, lack of knowledge about the available treatments or the absence of experts in the location where the patient is being treated. Much of the session focused on how these barriers are being overcome by partnerships between health care provides, employers and patients.
For example, new technologies such as DNA sequencing and other cell-based markers enable better diagnosis of a patient’s underlying disease. This information can be collected by a community hospital and shared with experts who work with the treating doctor to consider the best options for the patient. If patients need to access a specialty center for treatment, there are new models for the delivery of such care. Emphasis is placed on building a relationship with the patient and their family by surrounding them with a team that can address any questions that arise. The model of patient-centered care is being embraced by employers who are purchasing suites of services for their employees.
Patient advocacy groups have also supported efforts to get the best information about the patients’ underlying disease. Advocacy organizations have been building tools to connect patients with researchers with the aim of allowing secure and responsible sharing of medical information to drive the patient-centered development of new treatments. In a related initiative, the American Society of Hematology is creating a data hub for clinical trials for sickle cell disease. Collectively, these efforts are designed to accelerate new treatments by allowing critical data to be shared among researchers.
Essential Policy Infrastructure for Regenerative Medicine:
Session two dovetailed nicely with first discussion. There was continued emphasis on the need for additional evidence (data) to demonstrate that regenerative medicine treatments are having a significant effect on the patient’s disease. Various speakers echoed the need for patients in clinical trials to work with researchers to determine the benefits of treatments. Success stories with gene therapies in blood diseases were cited as proof of concept where treatments being evaluated in clinical trials are demonstrating a significant and sustained impact on diseases. Evidence of benefit is needed by both regulatory bodies that approve the treatments, such as the FDA, and by public and private payers / insurers that pay for treatments and patients that need to know the best option for their particular disease.
In addition, various speakers cited the continued proliferation of “unproven treatments” being marketed by for-profit centers. There was broad concern that the promotion of treatment where there is no evidence of effectiveness will mislead some patients and potentially harm the scientifically rigorous development of new treatments. Particularly for “stem cell” treatments, there was a desire to develop evaluation criteria that are clear and transparent to allow legitimate treatments to be distinguished from those with no evidence of effectiveness. One participant suggested there be a scorecard approach where specific treatments could be rated against specific indicators of safety, medical benefit and value in relation to alternative treatments. The idea would be to make this information widely available to patients, medical providers and the public to inform everything from medical decision making to advertising.
Communicating the Vision
The final session considered communication needs for the field of regenerative medicine. Patients and patient advocacy organizations described how they are using social media and other networking tools to share information and experiences in navigating their treatment options. Patient advocacy groups also described the challenges from providers of unproven treatments. In one case, a for profit “pop up” clinic had used the group’s videos in an attempt to legitimize their unproven treatment.
There was general consensus among the panelists that the field of regenerative medicine needs “trusted intermediaries” who can evaluate claims and help patients distinguish between high quality research and “snake oil”. These intermediaries should have the capacity to compile the most reliable evidence and utilize it to determine what options are available to patients. In addition, there needs to be shared decision making model where patients have the opportunity to explore options in an unbiased environment so they may make the best decision based on their specific needs and values.
Creating this kind of Navigation System will not be easy but the alternative is unacceptable. Too many vulnerable patients are being taken advantage of by the growing number of “predatory clinics” hawking expensive therapies that are both unproven and unapproved. We owe it to these patients to create a simple way for them to identify what are the most promising therapies, ones that have the highest chance of being both safe and effective. The roundtable discussion marked a starting point, bringing together many of the key players in the field, highlighting the key issues and beginning to identify possible solutions.
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.