MONROVIA>> Looking into Marian McGlocklin’s big bright blue eyes, she doesn’t seem to have a care in the world.
Just as any other 22-month-old shouldn’t.
But look at Marian’s mother, Sara McGlocklin, and she looks for a glimmer of hope in those eyes.
Marian was diagnosed with a rare, uncurable and ultimately fatal, progressive genetic disorder — Neimann Pick Type C (NPC).
Even as her sweet personality shines through, it’s hard not to think how this disease can drain the life right out of her within years.
“It’s hard to prepare for the future, if you don’t know what’s going to happen to her,” said Sara.
Though Marian was small when she was born, Sara and her husband Paul McGlocklin never imagined that her size may have been one of the first signs that their daughter was facing a fatal disease.
Eventually more symptoms began to present themselves after Marian was six months – slow development, enlarged spleen.
After more than a year of test after test, going from doctor to doctor, and with the continuing persistence of her parents for a diagnoses, the NPC gene mutation was discovered through genome sequencing in March.
Marian’s four-year-old big sister was also tested but cleared of the genetic disorder.
Despite receiving the devastating news, the McGlocklins would soon find a reason to fight. After reaching out to other NPC families, and learning more about current developments in research of the disease, there was hope.
They learned about a phase 3 trial treatment of cyclodextrin, VTS-270, which was showing signs of slowing, though not reversing, the progression of the disease.
“I felt like I could breathe again,” said Sara about learning about the treatment.
They rushed to get Marian on the treatment and hopefully give her at least one or more extra years than she would have had without it. Now, researchers are looking to young patients like Marian, to learn more about NPC and cyclodextrin as a treatment.
Niemann Pick Type C-1
The types of symptoms and even the timing of the onset of symptoms vary widely with NPC. Some symptoms can start before birth, while others start in older children and even up to adulthood.
NPC causes progressive deterioration of the nervous system. It is caused by a defect in lipid transportation within the cell interfering with the affected person’s ability to metabolize cholesterol. Large amounts of cholesterol accumulate within the liver, spleen, and brain which can lead to cell deterioration, then difficulty eating and breathing, and often seizures. The majority of people with early onset of NPC die by their late teens or 20s.
Some patients’ symptoms may be only neurological, others physiological, while others deal with both and a host of other symptoms and complications from the disease.
“It can present mostly as a coordination problem, or a thinking problem, and initially the patients don’t lose skills they just gain them at a slower rate. So, there are a lot of patients who are initially thought to have a developmental disability,” said Dr. Elizabeth Berry-Kravis, professor of pediatric neurology and biochemistry at Rush University Medical Center in Chicago. She is a co-PI, or co-investigator for the VTS-270 trial, and has been treating NPC patients for years, including Marian when she first began the cyclodextrin treatment.
Because of the variety of symptoms, a patient may not be properly diagnosed or misdiagnosed for years. It wasn’t until 1997 that scientists identified the gene responsible for causing NPC, thanks to the Ara Parseghian Medical Research Foundation which funded early research. The foundation, named after the notable Notre Dame football coach, was started after three of Ara Parseghian’s grandchildren were diagnosed and ultimately succumbed to the disease.
The Parseghians have been instrumental in several advances in research into the cause of the disease and trials for treatments.
Before the Parseghian Foundation, two labs were dedicated to NPC research. Now there are more than 20, and the foundation raises more than $2 million a year toward research.
Berry-Kravis notes there have been advancements in the way of diagnosing this type of rare disease in recent years.
“Before you had to know that you wanted to diagnose for NPC. It would take four to six years, where the patient would have enough of the symptoms to know what to look for,” she said. “Now we have this genome sequencing, and then it comes back with the NPC gene, and the clinician no longer has to know what they’re looking for.”
Early diagnosis is especially important for young NPC patients, who have a limited time before the disease begins to deteriorate their body. The earlier they can get treatment such as the cyclodextrin, the more effective it can be.
“If a patient is minimally affected earlier in their disease, they may do better than someone who has several symptoms already,” said Berry-Kravis. “You want to get it when the patient has almost no symptoms; but some don’t have them until they’re about 15.”
Cyclodextrins, made up of sugar molecules, are the foundation for the treatment VTS-270, currently developed by Maryland-based VTesse.
The treatment seems to be the only hope for many NPC patients. Though the human trials for VTS-270 is for ages 4 and up, the McGlocklins and some other patients successfully petitioned to get the treatment through a compassionate use program.
Before being approved for compassionate use at Children’s Hospital Los Angeles, Marian was flying out to Chicago to receive the treatment every other week.
So far, she has been the youngest to start the treatment, which is given intrathecal, or through the spinal cord. Her body is elevated head down for a time to help the treatment reach the brain. For now, the treatment has to be given every two weeks, indefinitely.
Researchers say giving the treatment through an IV does not help the treatment break the blood-brain barrier, and would not help patients like Marian, with neurological symptoms.
“We’ll be seeing her periodically, every 6 months or a year, to see her developments,” said Berry-Kravis about Marian. “What we’re interested in is her developmental projections. Mapping what her development does. Seeing if she catches up developmentally where she’s supposed to be.”
The McGlocklins said they have seen a marked improvement in Marian’s progress since beginning the treatment. She is bearing more weight on her legs, and learning to walk, a big step in her development, even at this stage in her infancy.
“She always seemed tired. Now she wants to play more,” said Sara McGlocklin. “We see more of her personality coming through.”
Marian even threw a bit of a tantrum once – something Sara said they were actually happy about because it showed she had enough strength to do it.
The trial will be over early next year and will then be presented to the Federal Drug Administration for approval.
Berry-Kravis said hopefully the trial data will show the FDA that it is effective enough for approval, and can help Marian and other patients continue the treatment, and not worry about finding another treatment or trial that may not be available. Hopefully the approval will also mean, the families can get help to cover the treatment costs.
“We’re trying to show there is a little bit better outcome,” she said. “The real thing that we need to know is whether the drug works over the long-term.”
The hope for NPC families is a cure, of course, but a hopeful treatment is a step in the right direction. And knowing the strength of the almighty dollar, families like the McGlocklins know the importance of funding the critical research that will help find a cure. The McGlocklins started a GoFundMe page soon after learning Marian’s diagnosis, and a blog, with the idea of spreading awareness of NPC and helping to fund research.
“(The research for a cure for NPC) is moving faster than some diseases, but it never moves fast enough for the families who are dealing with this disease,” said Berry-Kravis.
Sara said her goal, after the FDA approval and Marian’s continued progress with treatment, will be to ultimately push for newborn screening.
Earlier screening will hopefully mean more children being diagnosed early, avoiding misdiagnosis, and early intervention, for a lot more families.
The Chans of Diamond Bar
Even in utero, Galya Chan, was always behind her twin brother Ezra. Caris and Brian Chan’s twins were born premature in 2012. But while Ezra eventually was growing well, Galya still struggled to catch up developmentally and was dealt with several complications by the time she was six months.
After several complications, misdiagnoses, complicated surgeries, the Chans found out about Galya’s NPC when she was 13 months old. But it would be about six months before she began the VTS-270 treatment through compassionate use at Children’s Hospital Orange County in 2014.
“It was crazy because I didn’t have time to think, because it was fatal, I sprang into action,” said Brian Chan. “Within a split second, all the hopes you have for your child, those are all gone.”
Though Galya ended up getting cerebral palsy because of a complication during a biopsy surgery, Brian said he did notice improvements right away.
“Cyclodextrin has been a lifesaver. She’s able to sit up; physically she’s strong, which you don’t see with other NPC children,” he said.
Galya does need a feeding tube and is not able to walk on her own. She goes through physical therapy, just as Marian, who also does speech therapy.
One of the side effects of the treatment is hearing loss, which is also a symptom of NPC. So far Galya has not had any symptoms of side effects, though Marian recently began to show ultra high frequency hearing loss, but doctors cannot contribute that to the treatment or the disease.
Brian Chan, an entrepreneur with a software company, created another company, Galya Tech, to focus on gene therapy, “because we think that would fix the root of the problem.”
The Chans three other children, including Galya’s twin brother, were tested and shown to be carriers – they can pass on the disease to their children but they will not get symptoms.
Hope for a future
Sara McGlocklin always wanted to have three children, and despite the 25 percent chance another of their children will also have NPC, she said she hopes to one day continue to fulfill that dream.
But for now, the McGlocklins want to focus on their daughters; trying to have a normal life between treatments and therapy; and being advocates for Marian and NPC.
“I still feel worried. It can be a little depressing,” said Sara, who goes between feeling hopeful and being a realist in the uncertain future of Marian.
“I see a door opening, and it’s wonderful,” she said. “We know this is not going to be a cure. The proof will be in Marian.”
Brian Chan said he has two kinds of hopes – short term and long term.
“For my short term hope, getting the gene therapy but I realize that may not be in time for Galya,” he said.
So for his ultimate, long term hope, he leans strongly on his faith.
“When I look at my other healthy kids, they’re going to die one day, too, and my hope is that they will ultimately rise again,” said Brian. “So, my hope is that I will see her again in heaven and I will dance with her.”