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.

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.