With an aim of addressing a critical and unmet need in rare
disease research, CHOC Children’s will advance rare disease genome editing
therapeutics, thanks to a $1 million grant from The Larry and Helen Hoag
The funding will help form CHOC Children’s 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
Children’s 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 Children’s 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 Children’s 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 Children’s 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
Children’s 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 Children’s advance research for a rare lysosomal
storage disease, ultimately leading to an improved understanding and more
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 Children’s.
“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.