With an aim of addressing a critical and unmet need in rare disease research, CHOC will advance rare disease genome editing therapeutics, thanks to a $1 million grant from The Larry and Helen Hoag Foundation.
The funding will help form CHOC Center for Advancing Rare disease Editing (CARE), allowing researchers to further their work to use genome editing to rapidly generate, characterize and treat preclinical models of rare disorders with known pathogenic mutations.
Genome editing therapy has the potential to permanently
correct underlying pathogenic mutations in patients with some rare diseases.
This treatment addresses the root cause of the disorder, eliminating the need
for more standard therapies like enzyme replacement and stem cell
transplantation that often require repeated treatments.
“CHOC is at the forefront of operating at the interface of translational research and clinical care of rare disorders,” said Brent Dethlefs, executive director of the CHOC Research Institute. “Our ultimate goal is to provide patients with rare diseases with an objective, rigorous assessment of whether genome editing therapy has the potential to advance their current standard of care.”
The work will build upon CHOC’s existing successes in
developing preclinical models of rare diseases. For example, CHOC’s lysosomal
storage disorders research team has already generated the first preclinical
models of Pompe disease – a rare and fatal disorder that affects the heart and
muscles – that are suitable for genome editing therapy and exhibit molecular,
biochemical and functional analogy to patients with the severe infantile-onset
form of the disease.
“Given the success of this project, we have received
multiple inquiries from research colleagues seeking to collaborate and patient
advocacy groups hoping to generate additional preclinical models of rare
disease, but until now, we’ve never had the resources to participate,” CHOC
Jeffrey Huang said. “We believe that CARE has the potential for rapid
growth given the intrinsic scalability of genome editing as a strategy to
generate preclinical models and develop novel therapeutics.”
The Hoag Foundation funding complements a grant CARE recently received from the CHOC Foundation’s One Wish Grants awards. The grant awards unrestricted funds to outstanding ideas that drive advancement toward CHOC’s strategic goals.
The mission of The Larry and Helen Hoag Foundation is to educate, empower and create greater opportunity for at-risk children to become independent, productive and contributing members of society; support medical research and technology to enhance the health and well-being of children; and support such other compelling purposes that will enhance the quality of life for residents in Southern California.
Like most physicians, Dr.
Raymond Wang got into medicine because he wanted to help. He wanted to be
able to tell patients and their families that he could fix whatever was wrong
When it comes to the disease Dr. Wang dedicated his career
to studying, however, he can’t offer such assurances. Hopefully that day is
Dr. Wang and his team at CHOC are participating in a clinical trial of a drug intended to treat a rare pediatric disease called MPS IIIA. It’s a type of Mucopolysaccharidosis, or MPS, a genetic condition that causes physical abnormalities in young children and causes them to lose their neurological development.
Also called Sanfilippo syndrome, its early symptoms can mirror
those of autism, but unlike autism, the patients don’t improve, instead
gradually deteriorating until memories and even basic abilities are lost. Most Sanfilippo
patients don’t survive to adulthood.
There is currently no cure.
“When we go into medicine, we come in thinking, ‘All right, I’m going to help my patients. I’m going to make them better,’ ” says Dr. Wang, a clinical geneticist and biochemical genetics specialist at CHOC for the past 12 years. “When you are faced with the prospect that you can’t help, or at least in the sense that you can’t make these kids better and cure them, that doesn’t sit well with me.”
Phases II and III of the trial are being conducted by Lysogene, the French company that developed the experimental treatment. CHOC is one of four U.S. hospitals taking part; there are three such sites in Europe: in France, Germany, and the Netherlands. Lysogene is still enrolling patients and is seeking a total of 20.
Those patients are hard to find. In his decade of
researching MPS and seeing patients, Dr. Wang estimates he’s only diagnosed 10 cases.
Two of those children were siblings, and tragically both died of the disease.
But Dr. Wang has enrolled one patient in the new trial.
Lysogene sought out Dr. Wang for the trial because of his expertise in
researching and diagnosing the various MPS types. If the Lysogene drug is
eventually approved by the FDA, CHOC should become the first facility on the
West Coast to be able to both diagnose the disease and administer the drug,
which is surgically inserted into brain tissue.
It won’t be apparent until a checkup about six months after
the procedure whether the drug is working.
“We are hoping to prevent regression at the least, or allow
for developmental progression,” Dr. Wang said.
There have been seven different
types of MPS identified: I, II, III, IV, VI, VII and IX, not counting the
subtypes within them. The subtype MPS IIIA, Sanfilippo, strikes about one in
every 100,000 children.
MPS is an inherited disease.
All the types are collectively known as “lysosomal storage diseases.” Lysosomes
are compartments in cells that break down molecules and remove waste products.
different enzymes in the lysosomes break down complex sugars called
glycosaminoglycans, also known as mucopolysaccharides. In MPS,
glycosaminoglycans are not broken down because of a deficiency in one of those
lysosomal enzymes. As a result, the glycosaminoglycans accumulate in the cells
and cause tissue damage.
symptoms can include thickening of the lips and skin, enlarged liver and
spleen, hernias, recurring ear infections, joint pain and stiffness, and
shortness of stature. With Sanfilippo, which attacks brain cells, cognitive impairment
could include delayed speech. Since by itself speech delay isn’t uncommon in
children, Sanfilippo’s initial symptoms only add to the confusion for families.
In the first two to three years of a patient’s life, “there might not be any symptoms,” said Dr. Wang, director of CHOC’s Foundation of Caring Lysosomal Storage Disorder Program . “Nobody ever thinks ‘my kid has Sanfilippo,’ and few doctors think about it. But it starts to be around 3, 4, 5, when hyperactivity starts, and there are questions of autism, and usually what happens is a physician recognizes that kids with Sanfilippo look a little different.”
treatment that has shown success for some kinds of MPS is enzyme-replacement
therapy: delivering synthetic working enzyme using an intravenous solution. It can
reduce the effect of symptoms and improve quality of life. But the treatment
only works if the disease is not located in the brain; unfortunately, the
life-threatening symptoms of Sanflippo are caused by effects of the disease in
the nervous system.
the brains of children with Sanfilippo syndrome, a waste product called heparan
sulfate builds up, causing nerve damage and, over time, the death of nerve
cells. The Lysogene drug includes a package called a
“vector.” It contains genetic instructions that enable treated nerve cells to
make the missing enzyme, called sulfo-hydrolase, which clears out the waste
“Short-term, you can measure things like, is the body
producing sulfo-hydrolase enzyme; is there a reduction in heparan sulfate?” Dr.
Wang says. “But the more important thing is, is this actually helping these children?
What parents really care about is, is it helping their child’s neurologic
function. Is my child not regressing? Is my child maybe even gaining
developmental milestones back?”
Dr. Wang acknowledges that, as a younger doctor, he was fascinated by the diagnostic side, the “sleuthing” part of identifying patients with, and researching, MPS. But over time, after accompanying many MPS patients and their families along difficult and tragic journeys, he knows his motivations now have a higher purpose, beyond intellectual stimulation.
reflects that his involvement in clinical trials for children with
neurodegenerative conditions such as the Lysogene study is “a way for me
personally to channel my feelings of helplessness when we diagnose someone with
a supposedly incurable condition.”
“I know how painful it is for these families,” Dr.
Wang says. “If I can give them the possibility of hope, then that’s what makes
waking up each morning and heading to work worthwhile.”
Learn more about referring to CHOC’s metabolic disorders specialists.
An $8 million gift from the Foundation of Caring will help CHOC advance research for a rare lysosomal storage disease, ultimately leading to an improved understanding and more effective treatments.
The gift will support CHOC researchers working to develop next-generation therapies for Pompe disease, a lysosomal storage disease wherein glycogen builds up in the body’s cells and causes life-threatening heart failure and muscle weakness in affected babies. In honor of the gift, the program will be named the Foundation of Caring Lysosomal Storage Disorder Program at CHOC.
“This incredibly generous gift from the Foundation of Caring will help accelerate our work to unlock the challenges of Pompe disease and other lysosomal storage disorders, advancing our vision to develop permanent cures for patients with these conditions,” said Dr. Raymond Wang, a CHOC metabolic disorders specialist and director of the Foundation of Caring Lysosomal Storage Disorder Program. “We’re so tremendously grateful to have the Foundation of Caring’s support in CHOC’s goal to protect the magic of childhood.”
Dr. Wang’s work around Pompe disease
drew the attention of the Foundation of Caring several years ago, when he began
treating the great-granddaughter of the Foundation’s founder after she was
diagnosed with the condition.
With previous support from the Foundation
of Caring, Dr. Wang and his team have already made significant strides in its study
of Pompe disease, having built a growing research team that’s used CRISPR/Cas9
technology to edit the genome to create animal models of Pompe disease. The
Foundation of Caring’s gift will allow Dr. Wang and his team to expand upon
this work and use CRISPR to cure Pompe disease and lysosomal storage disorders.
“We are so pleased to support the
important work of Dr. Wang and his team at CHOC to help find better treatment
or, even better, a cure for Pompe disease for patients affected by the condition
worldwide,” said the Foundation of Caring Board of Directors.
The newborn baby girl arrived at CHOC Hospital with a life-threatening irregular heartbeat. Thwarting what could have become a medical odyssey to find a diagnosis, rapid whole genome sequencing (rWGS) pinpointed her condition within two days: Timothy Syndrome, an extremely rare cardiac condition that put her at risk for sudden death.
With the genetic diagnosis in hand, CHOC physicians were able to
treat the infant with a medication normally contraindicated for her condition.
Her heartbeat was restored to normal, significantly reducing the risk of sudden
cardiac death. Her physicians, secure in her diagnosis, implanted a pacemaker,
dramatically improving her chances for a happy and healthy childhood.
Now almost 1, this baby is one of nearly 150 critically ill
infants who have undergone rapid whole genome sequencing (rWGS) since fall 2018
as part of Project Baby Bear, a pilot project to save babies’ lives – in
addition to healthcare costs.
With five participating California children’s hospitals, including CHOC, Project Baby Bear has proven the medical and economic benefits of this most advanced and comprehensive diagnostic method.
Led by Rady
Children’s Hospital-San Diego, the program helps
infants who are undergoing intensive care and covered by Medi-Cal. By
pinpointing the cause of rare disease with rWGS, physicians can customize
treatment. Having a genetic diagnosis can eliminate the need for futile tests
and procedures while decreasing hospital stays. For parents and children, getting
a fast answer means less suffering and more peace of mind.
Physicians at CHOC Hospital recently administered the first ever in-human dosing of gene therapy for Hurler Syndrome, the severe form of mucopolysaccharidosis type I (MPS I), a rare and progressive lysosomal storage disease.
successful, the gene therapy could present an alternative treatment for Hurler
Syndrome, which currently calls for a stem cell transplant for children younger
than 2 ½. While stem cell transplants are well-proven to help prevent most of
the neurologic decline that happens to untreated MPS I patients, the procedure
poses significant risks.
Patients with MPS I have a
genetic mutation that leads to a deficiency in alpha-L-iduronidase. This enzyme
helps break down chemicals called glycosaminoglycans, specifically dermatan and
heparin sulfate, the buildup of which can ultimately cause enlarged organs and
tissues, heart valve thickening, spinal cord compression, hydrocephalus and progressive
loss of intellectual milestones.
The hope is that the gene therapy – RGX-111, which is produced by REGENXBIO Inc. – will equip the patient’s brain cells with the information needed to make working alpha-Liduronidase enzyme to stop the glycosaminoglycans from building in the brain, says Dr. Raymond Wang, a CHOC pediatric metabolic disorders specialist and the study’s lead investigator.
The therapy was
administered through a cervical puncture in the neck. With three-dimensional
visualization and guidance from a computed tomography scanner, CHOC
interventional radiologist Dr. Tammam Beydoun carefully inserted the needle into
the fluid-filled space at the junction of the spinal cord and brain stem. Then,
Dr. Wang administered the gene therapy.
“I could not have
asked for a better implementation of everything we had planned for many months,”
Dr. Wang says. “I am so grateful for such an awesome team of people working
together for one common goal.”
Dr. Wang says the patient will be monitored indefinitely, with clinicians tracking the child’s cognitive and physical development, as well as measuring the quantity of alpha-L-iduronidase in the child’s body and spinal fluid to determine whether glycosaminoglycans dermatan and heparin sulfate are being broken down.
“I cannot guarantee if the
gene therapy is going to work, but the alternative was to watch and let this
patient get worse and worse and worse,” said Dr. Raymond Wang. “We’ve got to
Babies with MPS I show no
signs of the condition upon birth. To this end, MPS I was added to the list of
conditions tested for in California’s Newborn Screening Program in 2018. But
even with enzyme replacement therapy treatment, recommended to begin before age
2, the disease continues to progress, Dr. Wang says.
“Patients will reach a plateau in developmental milestones, and then they’ll start losing milestones,” he says. “Once they could speak, they lose the ability to speak. Once they were able to walk, they lose ability to walk. Then it gets to be really heartbreaking: Once they could eat, then they can’t eat anymore.”
Many patients ultimately rely
on feeding tubes, while often enduring airway problems, cardiac disease and
hydrocephalus. Quality of life is typically poor, Dr. Wang says.
Not only could a
successful outcome in this investigation dramatically change the course of a
patient’s life, but it could also pave the way for future gene therapy for
additional patients with rare diseases at CHOC, Dr. Wang says.
“This is an opening chapter for a very cool story,” Dr. Wang says.
A CHOC nurse scientist will discuss the health system’s culture of collaborative innovation this month at a prestigious Cleveland Clinic conference, marking the first time outside organizations have been invited to present.
Hayakawa, DNP, CNS, CCRN, CNRN, will participate in a panel discussion titled
“Teamwork makes the dream work” at the seventh annual Nursing Innovation Summit on Oct. 23.
presentation, “Defending Childhood Through Collaborative Innovation,” Jennifer
will discuss the role of a nurse scientist; CHOC’s infrastructure to support
nurse innovation; and CHOC nurses’ collaboration with multidisciplinary teams while
in pursuit of innovation.
Multidisciplinary collaboration at
To illustrate the multidisciplinary collaboration at CHOC, Jennifer will also highlight a nurse-led innovation to study pediatric outcomes on a medical device that has been primarily used in adults. CHOC is among the first institutions worldwide to study the use of automated pupillometry in pediatrics. Pupillometers provide reliable and objective data to assist with early detection of subtle neurological changes.
pupillometry has been integrated into standard of care and clinical
decision-making in adult intensive care units across the nation,” Jennifer
says. “While there are multiple studies that validate the use of pupillary
metrics to improve clinical outcomes in adult populations, there are very few
published studies describing its use in children. Several children’s hospitals
are using it, but we’re the first to develop a robust database. Through that,
we’ve learned more about what works for our population and we have identified a
few challenges unique to pediatrics.”
The idea to begin collecting this data came from the pediatric intensive care unit nurses at CHOC – and has led to a valued partnership with the device manufacturer. Through that relationship, a CHOC multidisciplinary research team will soon begin evaluating the use of pupillary metrics in the assessment and management of concussion, Jennifer says.
help our industry partner to improve their product and will allow us to learn
more about application of this new technology in diverse clinical populations,”
she says. “We collaborated with the CHOC Research Institute and Innovation Lab to connect with lawyers to get advice about intellectual
property and data use agreement contracts. That’s the focus of the conference
and panel – working together to innovate healthcare – navigating all of those
panel, Jennifer will share the stage with a physician and a patent attorney,
and she’s thrilled for the opportunity.
collaboratively to innovate care is something I’m really passionate about,” she
The path to a research career
path toward becoming a nurse scientist at CHOC began about 18 years ago, when
she joined the organization as a unit secretary while in nursing school. Upon
graduation, Jennifer began work at the bedside in the pediatric intensive care
years, she transitioned to an educator role and later to a clinical nurse
specialist role. About two years ago, Jennifer
became CHOC’s nurse scientist.
thought I’d move away from the bedside,” she says. “But my career path and
professional growth has led to different opportunities.”
knew research was an important part of my role as a clinical nurse specialist,
but research always seemed daunting” she says. “Coming out of that program
changed my perspective and gave me the confidence to pursue my doctorate
Research isn’t done in a silo
In her role
today, Jennifer is charged with nurturing a culture of inquiry at CHOC.
Critical to that is building infrastructure, while also mentoring and guiding
nurses through the research process.
incorporates her experience as an intimated nascent researcher when working
today with nurses considering an investigation or embarking upon a new project.
“I tell them
they don’t have to do it alone,” she says. “Research and innovation isn’t done
in a silo; it’s done through a lot of multidisciplinary collaboration.”
As the role
nurses play in CHOC’s culture of inquiry continues to deepen, the results are
evident: In fiscal year 2019, CHOC nurses presented 31 posters and 24 podium presentations
at local and national conference and published five articles in peer-reviewed
“Research is integral to the care we provide at CHOC,” Jennifer says. “For families, it represents hope – hope for improved quality of life, hope for a cure, or hope to help other children and their families. It is an honor and a privilege to be a part of a team of talented people providing this innovative care.
Jeffrey Huang, Ph.D., a research scientist at CHOC Research Institute whose scientific interests include applying innovative molecular biology techniques to the treatment of rare pediatric disorders, was recently honored at the Molecular Medicine Tri-Conference. Considered one of the world’s leading international events in the field of drug discovery, development and diagnostics, the conference attracts more than 3,000 innovative thinkers and thought leaders in biotech, pharma and academia from around the world. In addition to serving as a guest speaker at the conference, Dr. Huang was honored with the “Best Poster” award for his presentation, “Engineering cellular and animal models of rare disease using CRISPR-Cas9 genome editing.” In this Q & A, he shares insight about his research and its promise for the future.
What inspires you to focus on rare pediatric disorders, such as Pompe disease?
As a translational research scientist, I am committed to bringing the best scientific research has to offer to the clinic. My decision to join CHOC Research Institute was fueled by a desire to address the lack of alternative treatment options for CHOC patients and families affected by rare pediatric disorders. Over 30 million Americans – nearly 1 in 10 people – suffer from one of the 7,000 conditions classified as a rare disease. Many rare disorders often lead to progressively debilitating and sometimes fatal outcomes in infants and children. Unfortunately, there are no cures for most rare diseases; if existent, current therapy only attenuates or slows disease progression. My primary research focus is to evaluate and develop CRISPR genome editing therapeutics to address deficiencies of existing treatment for rare pediatric disorders such as Pompe disease.
What are you seeking to accomplish with your research?
Currently, I lead a project to develop personalized CRISPR genome editing therapeutics for Pompe disease – our proof-of-concept rare pediatric disorder. Pompe disease is a progressive cardiac and skeletal myopathy lysosomal storage disorder (LSD) which, despite intravenous doses of recombinant enzyme 40 times that of other LSD treatments, results in the deterioration of affected patients’ muscle strength. With over 15 years of experience in advanced molecular, cellular, and developmental biology, I have outlined the following strategy to evaluate the therapeutic efficacy and safety of CRISPR genome editing for Pompe disease.
The specific aims of our project are:
1) To generate, via CRISPR-Cas9 technology, animal models of Pompe disease that bear mutations homologous to those that cause human Pompe disease
2) To fully evaluate and validate the animal models generated to ensure molecular, biochemical, histopathological and functional analogy to human Pompe disease
3) To develop specific CRISPR genome editing/delivery systems correcting mutations in validated models of Pompe disease
4) To assess molecular, biochemical, histopathological and functional efficacy as well as safety of CRISPR genome correction in our Pompe disease animal models
I am excited to report that within the past year we have successfully demonstrated that our Pompe disease-specific CRISPR genome editing strategy has produced the desired mutations in cultured cells. Following this pilot experiment, we microinjected our Pompe disease CRISPR reagents into fertilized mouse zygotes to produce the first CRISPR-generated animal model at CHOC (Specific Aim 1). We are currently expanding this new animal model of Pompe disease and will perform the appropriate tests on the expanded cohort to confirm analogy to human Pompe disease (Specific Aim 2).
Our newly generated Pompe animal models will form the basis for future studies that will test the efficacy and safety of CRISPR-mediated genome correction in an in vivo context.
What other projects are in the works?
Future work will focus on evaluating which CRISPR delivery strategy works best to correct Pompe disease mutations in affected tissue (Specific Aim 3) and assessing the efficacy and safety of genome correction in our animal model (Specific Aim 4). Our application of CRISPR technology to Pompe disease will form the basis for future personalized genome editing studies and model the appropriate safeguards that need to be taken prior to testing CRISPR genome editing therapies in a clinical setting.
CHOC’s new stem cell production facility, slated to open late this summer, will allow CHOC researchers to produce patient-specific cells for immune-matching therapies that could positively impact fatal neurological diseases in children – all at a fraction of the cost of building a larger, more complex laboratory.
Within the state-the-art softwall clean room, CHOC researchers will study a stem cell-based therapy for the treatment for mucopolysaccharidosis (MPS-1), a rare and progressive neurodegenerative disease that typically claims patients before they reach the age of 10.
“Based on the results of animal trials we’ve conducted so far, we have a high degree of confidence that stem cell-based therapy will work to treat MPS-1,” said Philip Schwartz, Ph.D., senior scientist at the CHOC Research Institute and managing director of the National Human Neural Stem Cell Resource.
“If our research is successful, the approach could be used to treat a number of other immune-based diseases that damage the nervous system, like multiple sclerosis,” Dr. Schwartz said.
The approach involves using umbilical cord blood to replace a patient’s immune system, then implanting neural cells derived from the same blood into the brain to repair and prevent brain damage.
While implanting cells directly into the brain isn’t new, current treatment protocols require that patients take immunosuppressant drugs to reduce the risk of rejection, which leaves them vulnerable to a host of infections. Standard procedures for replacing the immune system, like bone marrow transplants, aren’t effective for patients with brain disorders caused by their underlying disease because the transplanted cells don’t cross the blood-brain barrier and therefore don’t slow the progression of brain disease.
The new facility will be one of less than a dozen in the nation and the only one that is focused on immune matching rather than immune suppression.
Dr. Schwartz estimated that it would require about five years of work to establish a program before approaching the U.S. Food and Drug Administration for approval to begin Phase I clinical trials. The current research project is supported by a $4.27 million grant from the California Institute for Regenerative Medicine.