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Aaron Vincent Elkaim/The Globe and Mail

In the basement of their Pickering, Ont., home, five-year-old James Marcogliese and his six-year-old brother, Daniel, practically bounce off the walls of their den-turned-classroom. The two boys proudly show off their twin fishbowls (one conspicuously fish-free), their rack of Avengers costumes and the anatomical diagram pasted to the wall.

“That’s the liver,” says James, who knows more about his own internal organs than any kid should. When James was born, an enlarged liver was the first sign something might be wrong. He was kept in intensive care for 10 days at Mount Sinai Hospital in Toronto while doctors investigated. The boys’ father, Paul, wasn’t yet overly concerned—Daniel also had a big belly as a baby.

The family soon learned why.

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Both boys were diagnosed with an ultra-rare genetic illness neither parent had ever heard of. Doctors told Paul and his wife, Cheryl, to make the most of the remaining time with their children. There was some sense to this advice. There are almost no approved drugs available for treating Niemann-Pick disease type C (NPC) anywhere in the world. It’s always fatal and many of its victims don’t live to see their 10th birthdays. Niemann-Pick is also known as Childhood Alzheimer’s, a kind of juvenile dementia that results from a gradual loss of basic function, speech and mobility.

Aaron Vincent Elkaim/The Globe and Mail

As a bond fund manager, Paul’s job is to provide stability amid chaos and impose order on the complex and random. Now he was being told to resign himself to a fate that was simply too terrible to accept. So he and Cheryl committed themselves to the world of rare-disease research.

Combining his financial acumen with the health-care sensibility she honed as an occupational therapist, the couple started to craft a plan: They would immerse themselves in a non-profit organization dedicated to fighting NPC, connect with the world’s foremost experts in the disease, access the best therapeutic drugs to manage symptoms, mine their connections for charitable donations, find and fund the most promising lines of medical research, cure the disease and save their children’s lives.

“We’re not in denial,” Paul says. “I know the odds are very much against us. As a mathematician, I very much understand that. But we’re going to do everything we can for those odds to change—and change dramatically.”

Niemann-Pick disease type C undermines the body’s ability to move and process cholesterol, which accumulates in the cells of various organs, including the liver and brain. This buildup eventually impedes brain function, slowly robbing otherwise healthy children of the ability to walk and talk, and ultimately to swallow and even breathe.

For the disease to occur, both parents need to be carriers, meaning they each have the same genetic mutation but exhibit none of the symptoms. Even then, there is only a 25% chance that two carriers will have a child with NPC. There are about 500 known cases worldwide, and its incidence is thought to be roughly one in 100,000 live births—comparable to the lifetime odds of being killed by a lightning strike.

For the Marcoglieses, the grief and despair of the diagnoses was compounded by the realization that mainstream medicine only has so much to offer for a disease this rare. Pharmaceutical companies generally require a certain volume of patients to justify the time and expense of developing a drug and then testing it, steering its approval for commercial use and bringing it to market. For the most part, the focus is on disorders with at least 10,000 cases. With only 150 to 180 NPC patients currently living in the United States, just finding enough cases to run clinical trials is difficult, says Sean Kassen, director of the Ara Parseghian Medical Research Fund at the University of Notre Dame in Indiana. (The organization is named after the legendary Notre Dame football coach who lost three grandchildren to NPC.) “That makes it very hard to get a drug approved for a rare disease, so pharmaceutical companies tend to avoid them,” he says.

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As the Marcoglieses started researching treatment options, they learned of an experimental drug called VTS-270 under development by Mallinckrodt Pharmaceuticals, a small U.S. drug company. Studies showed promise in the drug’s ability to stabilize NPC symptoms, essentially by cleaning up excess cholesterol in brain cells when administered by spinal injection. While the drug had not yet been approved by the U.S. Food and Drug Administration, it was accessible in the States through a compassionate-use program if the family crossed the border for treatment.

For two and a half years, the Marcoglieses flew to Chicago every two weeks for spinal infusions under anesthetic—87 and counting for Daniel, 44 for James. By age four, Daniel had been on so many flights, he earned Air Canada’s 35,000-mile status. “They almost never complain,” Paul says. “They complain more about getting their tablets taken away than any of the medical stuff.”

But losing access to the drug has been a constant threat. When the pandemic hit last year and cross-border flights virtually ground to a halt, Paul and the boys’ doctors urged the drug company to allow the treatment to be administered in Canada. They got the okay; the boys have been receiving their injections at the Hospital for Sick Children in Toronto ever since. Then in January, Mallinckrodt announced it was dropping the drug entirely. “We share in the disappointment of the entire NPC community,” the company wrote in letters to families. “[But] the risks associated with the treatment outweigh the potential benefit.” The drug can impair hearing in children like Daniel, who now needs hearing aids.

Families dealing with NPC say their children are living proof the drug works. While the disease can’t be neutralized, the treatment does delay the tightening of its grip, Paul says. Daniel’s speech is a little behind, and his balance isn’t perfect. He’s also become aware of his own limitations. “He’ll say, ‘Daddy, I don’t think I can do that,’” Paul says. He recently learned to ride a bike and is happy to slowly pedal around. His little brother is more likely to take a corner too fast and wipe out. “Everything James does is at full speed,” Paul says. “Unfortunately, we’re starting to see very small disease progression in him, but he doesn’t let it slow him down.”

There is enough supply of the drug to keep injections going until October. “It won’t take too long for the disease to take hold after treatment stops,” Paul says. The race is on to find a replacement. There is another development-stage drug, called arimoclomol, currently working its way through the approval process in the U.S. It has been effective in preventing the buildup of cholesterol at the cellular level.

When and if the drug will come to the Canadian market is unclear. Unlike the U.S. and European Union, Canada does not have a regulatory framework for the authorization of rare-disease pharmaceuticals, also known as orphan drugs. Patient advocates have long complained that regulatory and pricing barriers deter drug companies from introducing life-changing medicines to the Canadian market. Most orphan drugs are launched in Canada many months after they’re available in Europe and the U.S., while some never make it here at all. Since treatments for rare disorders tend to be exorbitantly priced—typically costing six figures per year, per patient—paying for these drugs out of pocket is not an option for most Canadians.

One way or another, the Marcoglieses are determined to access arimoclomol. Enabling their sons’ development to progress as much as possible will provide more runway when symptoms start to worsen. Aside from drugs, challenging them physically and cognitively is another way of holding back the disease. To that end, Daniel and James have also started treatment at Holland Bloorview Kids Rehabilitation Hospital. But access to NPC drugs is crucial in order to buy time while the science progresses. “If we could just know that the drug is going to be available to us for an extended period of time, we can put all of our energy into finding a cure,” Paul says.

Soon after James and Daniel tested positive for NPC, their parents paid a visit to the chair of the Canadian chapter of the National Niemann-Pick Disease Foundation, handing her a stack of cheques collected from family and friends. But the organization was pretty much dormant by that point. It’s a common story in the rare-disease space. Families directly affected by an illness become the fiercest advocates. When their loved ones succumb, some lose the will to continue the fight.

The Marcoglieses took over the foundation, cleaned up its structure, rebranded, incorporated and started raising money. Figuring out how to spend it was another matter. They joined the ranks of citizen-scientists—family members of people with rare disorders who help drive the research. “There’s a network of parents who have really begun to understand the disease at such a level that we’re intertwined with the scientists and we’re all talking together,” says Cheryl.

For researchers to qualify for major grants, the science typically already needs to be fairly advanced. That’s generally not a problem for the most common afflictions, like cancer or heart disease. Even better-known rare diseases, like muscular dystrophy or ALS, have lots of support from big donors, celebrities and the corporate sector. In the ultra-rare space, families like the Marcoglieses have had to fill the void.

“Family foundations, and parent-advocacy groups raising funds for supporting research, in my mind, have become an anchor of the rare-disease field globally,” says Ronald Cohn, president of SickKids Hospital. The lab bearing Cohn’s name at SickKids investigates treatments for rare genetic diseases, including NPC, using cutting-edge gene-editing and gene-therapy technologies. “Family foundations allow us to take a creative idea that maybe only has a small amount of preliminary data to check whether our ideas work,” Cohn says. If a thesis is proven right, that often paves the way for additional support through more common medical research funding avenues, like federal grants.

The Marcoglieses started their crash course in genetic disease by attending medical conferences and meeting with scientists. Pretty quickly, they started to identify where there were gaps in the research. “Family foundations have a sense of urgency,” Cheryl says. “So we’re willing to try anything, as long as there’s a scientific idea that makes sense.”

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Last year, a University of Michigan scientist who was working with the Marcoglieses approached them with a novel idea. He suspected the NPC gene affected liver cells in a different way than brain cells. If he was correct, it could change the way the disease is treated with targeted therapies. All he needed to test his theory was four stem cells, each costing US$15,000. To Paul, who runs a fixed-income portfolio at CI Global Asset Management, the numbers made sense. Relative to the price tag, the potential scientific upside was substantial. “One of my most useful skills in all of this is understanding the risk-reward paradigm,” Paul says. The experiment was a success and led to a grant with the National Institutes of Health—the U.S. government arm responsible for biomedical research.

Niemann-Pick Canada has now been running for about four years and has raised $2.7 million, much of it coming from Bay Street—banks, brokerages and asset managers Paul has marshalled to the cause. The foundation is currently funding three major lines of research. “How fast they’ve been able to do all this has been amazing,” Notre Dame’s Kassen says. “They’ve been a blessing to the NPC community.”

At SickKids, Niemann-Pick Canada is supporting Cohn’s lab in using the gene-editing technique called CRISPR, which enables unwanted genetic material to be removed. The “moon shot”—a cure for NPC—is the ultimate goal, Cohn says. But it’s not the only measure of success. “If we could find a therapy that could help us even halt the disease and prevent it from getting worse, that would be a game-changer,” Cohn says. “I’m hopeful.”

For NPC, there are at least 300 different mutations associated with each gene inherited from two parents. In a child, those mutations can combine in countless ways, only some of which are harmful. The SickKids team’s first goal is to figure out which combinations of mutations are disease-causing. They’re even working with Daniel and James’s specific mutations, which were determined through genetic testing. While it’s still relatively early days for the science, many researchers believe the technique could eventually eliminate a variety of inherited disorders, from cystic fibrosis to hemophilia. “We’re moving the needle,” Paul says. “At some point, there’s going to be a breakthrough.”

For someone who sees things through a math and finance lens, the numbers alone are haunting. The risk of NPC is so low as to be non-existent. But not only has lightning struck the Marcogliese household; it has struck twice.

There’s not a lot of time to wallow. The boys need their injections twice a month. There’s a foundation to run. Other families across Canada—newly devastated by an NPC diagnosis—need someone to talk to and walk them through their options. There are donations to drum up, finances to track, scientists to keep up with. There are politicians to lobby, drug companies to solicit, research papers to read. Paul and Cheryl both have full-time careers, in addition to all the effort involved in raising two young children. Still, Paul aims to finish work by 4 p.m. so he can go downstairs and play video games with Daniel and James before dinner.

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Aaron Vincent Elkaim/The Globe and Mail

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