Fresh Hope for Treating a Rare Progressive, Lysosomal Storage Childhood Disease


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It took nearly a decade and the loss of two infants before Khalid and Jabin Shaikh finally learned what was going wrong. Their third child, Zain, a son, was born in 2007 and immediately whisked away to a pediatric hospital for testing in an effort to identify the disease that took the lives of his siblings. While Zain survived infancy and beyond and met his major developmental milestones, it still took years of testing and inconclusive interpretations of unusual test results before the Shaikh family finally heard of Niemann-Pick Disease Type C (NPC).

Getting this diagnosis for Zain was a critical step for the Shaikh family, but solutions were still lacking. There is no cure for NPC. This genetic neurodegenerative condition is progressive, irreversible, and chronically debilitating. It is caused by a defect in lipid transportation within the cell, which leads to excessive accumulation of lipids in the brain, liver and spleen. It can lead to difficulty eating and breathing, and often seizures. The majority of people with NPC die by their late teens or 20s. Was the Shaikh family destined to lose their surviving child, too?

“I have been pulled to this place,” said Khalid Shaikh, who is now taking a sabbatical year from his job in the software industry in his native India to be in Philadelphia with his wife and son, pursuing a new hope for a better outcome for Zain.

Now a quiet 9-year-old with deep brown doe eyes, Zain is one of just over 50 children in the world are enrolling in an international multi-site clinical trial of an investigational treatment for NPC sponsored by Vtesse Inc. He is the first to enroll at the study site at The Children’s Hospital of Philadelphia in this Phase 2b/3 clinical trial.

“We are feeling very confident that CHOP will successfully help this child to better health because some power, some almighty, is planning this stuff,” Khalid said. “Very few families get an opportunity like this.”

There is no FDA approved therapy for NPC, and most interventions only help manage its symptoms, which can vary across a broad spectrum. Sometimes the condition initially appears as liver disease detected in newborns or even during fetal development. A majority of children with NPC have an eye-movement symptom called vertical supranuclear gaze palsy, in which children are initially slow to shift their gaze to look up, and control over eye movement degenerates over time due to neurological damage. Often, children exhibit problems with neurological development and experience progressive losses after initially appearing to be healthy for the first few years of life.

“You have a walking child, all of a sudden, losing milestones,” said Can Ficicioglu, MD, PhD, director of the newborn metabolic screening  and lysosomal storage disease programs at CHOP and associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, who is the lead investigator for the CHOP site of the NPC trial.

Zain Shaikh, so far, has been lucky. He has full control over his movements and showed relatively few symptoms of NPC until he had major seizures within the last year. More subtle symptoms affecting his intellectual development may have impacted his behavior and academic performance at school. For some children with NPC, belligerent behavior is an early sign that is misdiagnosed as a behavioral disorder until ongoing major cognitive decline makes it clear they are experiencing serious neurological degeneration.

NPC causes such brain damage as a result of one of two possible genetic mutations that affect how cells store cholesterol. By mechanisms that have not yet been fully explained, cholesterol and other lipids become trapped inside brain cells due to the mutated gene’s dysfunctional protein product; as a result, patients experience severe neurological decline.

The clinical trial for NPC is evaluating a drug candidate called VTS-270, which is a well-characterized mixture of 2-hydroxypropyl-beta-cyclodextrin (HPbCD) with a specific compositional fingerprint that distinguishes it from other HPbCD mixtures. Other versions of cyclodextrins have already been shown to be useful in medicine (such as sugammadex [BRIDION, Merck]), as well as different and entirely unexpected places such as the odor-neutralizing ingredient in Febreze.

In cell culture, VTS-270 has been shown to remove cholesterol from cells, so scientists have studied its potential as a treatment for NPC. Intrathecally injected VTS-270 has been shown to slow the disease in animal models. Last year, a team of researchers from multiple institutions including the University of Pennsylvania School of Veterinary Medicine showed that cats that have a naturally occurring version of NPC had dramatic improvements after treatment with VTS-270. Hearing loss was a side effect in cats and impact on high-frequency hearing is an expected side effect in children, although this effect is ambiguous; due to the neurodegeneration involved in NPC, some hearing loss may result from the disease itself. The translational step of testing as a veterinary therapy for affected cats was essential in establishing that the compound was safe enough to proceed with the clinical trials in children that are underway at sites worldwide, now including CHOP.

“When I talk with physicians who have been treating patients with this compound, they told me that it does something for affected kids,” Dr. Ficicioglu said. “But of course it is not a miracle. Since there is no treatment available, whatever you have is extremely promising.”

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