CHOC earns $1 million grant to advance rare disease genome-editing therapy

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 Foundation.

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 scientist Dr. 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.

Learn more about the CHOC Children’s Research Institute.

CHOC joins drug trial for rare disease that devastates families

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 with them.

When it comes to the disease Dr. Wang dedicated his career to studying, however, he can’t offer such assurances. Hopefully that day is coming.

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.”

Dr. Raymond Wang, CHOC Children’s clinical geneticist and biochemical genetics specialist

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.

Normally, 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.

Physical 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.”

A 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.

Inside 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 product.

“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.

He 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.

CHOC receives $8 million to advance research for rare disorder

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 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 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. Raymond Wang, CHOC metabolic disorders specialist, director of the Foundation of Caring Lysosomal Storage Disorder Program

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.

Learn more about the Foundation of Caring Lysosomal Storage Disorder Program at CHOC Children’s.

Offering answers, hope through rapid whole genome sequencing

The newborn baby girl arrived at CHOC Children’s 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 Children’s, 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.

The other participating hospitals include: UCSF Benioff Children’s Hospital Oakland, UC Davis Children’s Hospital in Sacramento, and Valley Children’s Healthcare in Madera.

Here’s a breakdown of each site’s cases and diagnoses, as of August 2019:

Here’s a look at Project Baby Bear by the numbers:

  • July 2019: project funded
  • $2 million: California state funding
  • 5: Number of participating hospitals statewide
  • 150 approximate infants sequenced
  • 182 hospital days avoided
  • 3 to 4 days: Ultra-rapid results turnaround
  • 3 to 7 days: Rapid results turnaround
  • 6 million children on Medi-Cal
  • 150,000 children could benefit from rWGS

Learn more about the CHOC Children’s Research Institute.

CHOC performs first in-human gene therapy dosing for MPS I

Physicians at CHOC Children’s 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.

If ultimately 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 procedure required five months of planning across disciplines at CHOC, including pediatric metabolic disorders, radiology and imaging, nursing and pharmacy, the pediatric intensive care unit and the CHOC Children’s Research Institute, as well as additional radiology expertise from another institution and support from REGENXBIO.

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.

(From top left, clockwise) Investigational pharmacist Winnie Stockton, radiology technologist Lesley Mercado, radiology technologist lead Nadia Casarrubias-Garcia, clinical research coordinator Eric Rodriguez, clinical research supervisor Nina Movsesyan, director of imaging services Windy Broking, pediatric metabolic disorders specialist Dr. Raymond Wang, interventional radiologist Dr. Tammam Beydoun and radiology medical director Azam Eghbal are part of the large team at CHOC Children’s who facilitated the procedure. The team also includes members of the radiology scheduling, information systems, health information management, research and nursing teams.

“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 try something.”

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.

Learn more about research at CHOC Children’s.