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.

CHOC at forefront of treating Batten disease

Bringing new hope to patients and their families, CHOC Children’s is now among a few hospitals in the country to offer treatment for a rare genetic brain condition that has previously been considered a death sentence for children.

CHOC has been fast tracked to commercially provide Brineura, the first and only treatment for CLN2 disease, also known as late infantile Batten disease. The condition typically begins with language delays and seizures before age 3, and rapidly progresses to dementia, blindness, loss of the ability to walk and talk, and death in childhood.

Bringing Brineura to CHOC is the product of three years of work by metabolic specialist Dr. Raymond Wang.

Dr. Raymond Wang, who treats patients with Batten disease, stands in lab looking over papers
Dr. Raymond Wang, CHOC metabolic specialist

“This is huge,” Dr. Wang says. “You’re taking a progressive and fatal disease and stopping it. Having seen how heartbreaking it is for families to see the child they know get slowly robbed from them, the fact that we can offer these families hope, is tremendous. Something like this is the very reason I went into medicine and specialized in metabolic disorders: to provide hope to families affected by rare disorders such as late infantile Batten disease.”

Dr. Wang works closely with CHOC neurosurgeon Dr. Joffre Olaya to administer the medicine. Each patient has an Ommaya reservoir implanted under their scalp, which allows the medicine to be infused directly into their brains.

In a sterile procedure every two weeks, Dr. Olaya and a team of highly trained nurses insert a needle into the reservoir to administer the medication. The infusion lasts four hours, and after four hours of observation, the patients can go home.

While not a cure, the drug can slow the progression of the disease. Over a three-year period, patients treated during clinical trials showed no progression of the disease, which was radically different from the disorder’s natural course. The medication improves quality of life and buys patients critical time as researchers continue to search for a cure.

Having the treatment available close to home is a game changer for the Bowman family.  A participant in the clinical trial, Ely Bowman, 4, would travel every 10 days with his parents from Orange County to Columbus, Ohio, for treatment.

But now, the Bowmans need only to drive a few miles to CHOC for this critical treatment.

“For Ely to be home and have consistency and we can still have some fun is wonderful,” his mother, Bekah, says. “We can see him thriving.”

Learn more about CHOC’s metabolic disorders division and the CHOC Children’s Neuroscience Institute.

Refer a patient for a metabolic disorder evaluation.

 

CHOC Metabolic Specialist Profiled in Science Magazine

The work of a CHOC Children’s metabolic disorders specialist and is highlighted in a recent Science magazine article.

The article hinges on Dr. Raymond Wang’s work to help a patient with a rare condition called Niemann-Pic Type C, a condition that causes cholesterol to accumulate in the brain, lungs, liver and spleen, leading to deterioration and early death.

Not only is the young girl doing well after Dr. Wang began an experimental treatment, but her family’s foundation also provided funding that allowed Dr. Wang to continue research that could help children with a rare metabolic diseases called mucopolysaccharidoses, or MPS.

To that end, the piece examines the tug of war felt by some physicians when balancing patient care and research. Despite a physician’s strong interest and commitment, research eludes many due to a lack of time and funding.

Read the full article in Science magazine.

Meet CHOC’s Specialists: Metabolic Disorders

It should come as no surprise that Dr. Jose Abdenur’s favorite fictional M.D. is Gregory House, television’s sleuthing physician known for deducing elusive diagnoses.

After all, Dr. Abdenur serves as chief of CHOC Children’s Metabolic Disorders Division, which specializes in diagnosing rare conditions that reMetabolic groupquire hours of unraveling symptoms, researching cases and analyzing data to give parents long-sought answers to what’s ailing their child.

“What we do often begins a life-long treatment,” says Dr. Abdenur. “These conditions create a bond with the family and our staff.”

Dr. Abdenur leads a group of about 20, including himself and two other physicians: Richard Chang, M.D. and Raymond Wang, M.D. Comprised of a clinical team and laboratory team, CHOC’s metabolic disorders division is large compared to other similar divisions at other hospitals, and remains in high clinical demand, the physicians say.

The division’s most commonly treated conditions are glycogen storage diseases, mitochondrial disorders, urea cycle defects, fatty acids oxidation defects and organic acidemias. CHOC metabolics is also the largest referral center in California for metabolic diseases detected by newborn screening.

And the division continues to expand: In mid-January, the division opened a new laboratory focusing on energy metabolism. There, researchers will study patients who have defects in energy production, underscoring the division’s commitment to broadening its understanding of metabolic disorder subsections.

A team- and family-centered approach

A core principle for the division is teamwork. No matter their position, each member of the division plays a vital role in diagnosing and caring for children with rare, often lifelong conditions, Dr. Abdenur says.

“We can’t do what we do without dieticians, genetic counselors and case managers for every single case,” he says. “We need everyone.”

Weekly, the team sees about 45 patients on an outpatient basis, operating several clinics, including the multidisciplinary lysosomal and neurometabolic clinics. The division treats between five and 10 patients a week on an in-patient basis.

Persistence is a chief value for the division. Tenacity is essential because the path to diagnosing a metabolic disorder can be a long and hard, and sometimes a dead end, says Dr. Abdenur.

“I never tell a family that for sure I’ll find out what’s wrong, but for sure, we will look as hard as we can,” he says.

Metabolic disorders physicians are sometimes charged with telling parents nothing more can be done for their child’s condition. And though not ideal, that news can bring solace to a parent, Dr. Abdenur says.

“Even when they know there is nothing more to do, there is a relief,” he says. “That way, they’re not still always wondering if they’re missing something.”

Recognizing that, the division places a keen focus providing family-centered care: Close parental involvement is key during diagnosis and treatment, which often lasts a lifetime. The division also hosts regular family events to provide education and activities for patients and families, as well as nutritionally appropriate treats and recipes.

A focus on research and education

While patient care is the top priority for the division, research and education also remains a central focus for the division.

CHOC metabolics partners with UCLA, Cedars Sinai and Harbor UCLA in a post-graduate program that offers genetics research training opportunities and is supported in part by a grant from the National Institutes of Health. Dr. Abdenur serves as its program director for medical biochemical training programs, and training director for clinical biochemical genetics.

The division also has a relatively new fellowship program. The program is designed to help train future metabolic disorders specialists, says Dr. Chang, noting that in the last round of metabolics certifications, fewer than 20 specialists earned the distinction nationally.

“Metabolics is a specialty that not all children’s hospitals have, and we’re trying to help improve access by training people in the field,” says Dr. Chang. “We’re trying to compensate for the shortage of metabolics physicians.”

The division is also working to broaden metabolics knowledge for CHOC nurses. An upcoming one-day conference made possible by the donation of a family of a metabolics patient will offer nurses more information about various metabolics disorders, as well as insight into the plights of patients and their families.

This is one in an occasional series introducing CHOC Children’s specialists. Learn more about how to refer patients to CHOC.