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Orphan Disease Seeks Parents, Funding

April 25, 2015
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Research on rare pediatric diseases often remains underfunded and obscure until motivated families give scientists — and their own children — a much-needed shot at potential therapies worthy of federal funding.

Reagan McGee’s pediatrician couldn’t figure out why she had cold after cold. Her parents, Karin and Peter McGee, took her to an ear, nose and throat specialist who discussed adenoids and ear tubes, but then said their girl didn’t quite resemble either parent.

“Coarse features, he called it,” Peter McGee says. The doctor suggested they see a geneticist.

The geneticist ordered X-rays that revealed suspicious features in Reagan’s bones. A blood test confirmed she had something they’d never heard of: Sanfilippo syndrome type A.

“We thought we had a healthy baby and then we find she has a terminal disease,” Karin McGee says.

The McGees grieved.

Then they dove into the scant Sanfilippo literature.

KNOW YOUR ENEMY

Children with Sanfilippo syndrome develop then degenerate, losing the ability to speak, walk and eat. Most die between age 10 and 20. The cause is a mutation to a gene that normally makes an enzyme that breaks down and disposes of mucopolysaccharides, long-chain sugar molecules essential to building connective tissues. When the molecules accumulate in cells, they cause progressive damage to organs and the central nervous system.

Sanfilippo syndrome is one of nearly 7,400 diseases classified as “rare” or “orphan” by the Centers for Disease Control and Prevention. They’re called rare because they afflict fewer than 200,000 people in the United States and orphan because drug companies historically found them too uncommon to invest in. Nearly 95 percent of these diseases currently have no cure.

Researchers recently compiled a list of about 130 patients with the most common two forms of Sanfilippo. They believe it includes the majority of U.S. children with the disease.

Online, the McGees found the O’Neill family in South Carolina, whose daughter Eliza was also in early stages of the disease. The O’Neills raised nearly $2 million for clinical trials with a video of Eliza that went viral. The McGees created their own nonprofit foundation, named Reagan’s Hope: A Cure for Sanfilippo, which has raised $30,000 in less than a year.

“You have to be out there,” Karin McGee says. “There’s no mega-foundation bringing in millions and millions of dollars.”

While Peter slept one night, Karin was on the computer and saw local Columbus, Ohio, experts were working for a Sanfilippo cure. She emailed Kevin Flanigan, MD, a neurologist and principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s Hospital.

Dr. Flanigan responded within minutes. They talked about the disease, Reagan and plans to test new treatments in clinical trials.

For the first time in a long time, the McGees felt hopeful.

A DOCTOR-PATIENT ALLIANCE

“When you work with rare diseases, it can be a very small community, and we rely on each other,” Dr. Flanigan says.

Parents need experts to advise them, treat their children and seek cures, and researchers need parents and patients in order to do their work.

“We turn to their foundations to fund early research that the National Institutes of Health and pharmaceutical companies show limited or little interest in,” Dr. Flanigan continues. “We wouldn’t be here at all without the foundations.”

Dr. Flanigan and his team — which includes Kim L. McBride, MD, MS, a geneticist and principal investigator in the Center for Cardiovascular and Pulmonary Research in The Research Institute at Nationwide Children’s — will test therapies that have been more than a decade in the making.

The two gene therapy approaches were developed by Haiyan Fu, PhD, and Douglas M. McCarty, PhD, principal investigators in the Center for Gene Therapy, and will target the two most common forms of Sanfilippo syndrome: types A and B.

The experimental therapeutic uses a modified virus to cross the blood-brain barrier. They hope that with one injection, the virus will deliver corrected genes and enzymemaking supplies to cells in the central nervous system and organs throughout the body. A single injection strikingly improved the health of mouse models of Sanfilippo.

Their early work was funded through an NIH grant to Dr. Fu. But since 2003, they have received continuous generous support from the Sanfilippo community through Ben’s Dream — The Sanfilippo Research Foundation. And since 2010, The Children’s Medical Research Foundation, Inc. (A Cure for Kirby), Sanfilippo Children’s Research Foundation (A Life for Elisa), Team Sanfilippo and LivLife have provided funds to accelerate the work. The team’s successes have drawn additional NIH funding into the mix to support moving these therapies towards their planned clinical trials in children with Sanfilippo disorders.

To scale up production of therapies for a clinical trial, Nationwide Children’s Office of Technology Commercialization reached out to an entrepreneur already commercializing another therapy developed at the hospital.

Abeona Therapeutics was formed to quickly move the therapies, called ABX-A and ABX-B, to the initial round of testing in patients. Abeona licensed the technology and is raising money; 15 Sanfilippo foundations from around the world have already invested. Drs. Fu, McCarty, McBride and Flanigan work closely in preparation for the first clinical trials, which will take place at Nationwide Children’s.

This path to a new orphan drug is well worn.

“Throughout the history of the rare disease community, patients and patient groups have played an enormous role in research,” says Mary Dunkle, vice president for Educational Initiatives at the National Organization of Rare Disorders.

NORD was created to help those with orphan diseases and the organizations that serve them. Its founders were drivers behind the 1983 Orphan Drug Act. In the decade prior, 10 treatments for rare diseases were brought to market. Since then, 460 have made it. Most often, patients and their families fueled the drive for these new treatments, Dunkle says.

The Orphan Drug Act provides tax breaks and other financial incentives for drug- and device-makers to serve a smaller population of patients. Such drugs as Cerezyme® to treat Gaucher disease, Soliris® for paroxysmal nocturnal hemoglobinuria and Elaprase® for Hunter’s Syndrome cost $300,000 to $440,000 per patient annually and showed that orphan drugs could yield a return on investment. But by and large, big pharmaceutical companies have only recently shown interest.

VERSATILITY REQUIRED

Just as orphan diseases force parents to take on the roles of fundraiser and advocate, they require doctors to fill many needs.

Dr. Flanigan treats patients, does scientific research, oversees clinical trials, consults as a member of orphan disease advisory boards and reviews grant applications for other proposed research in the field. He’s an educator who talks at parents’ meetings and hosts intensive training each year for new doctors. For Duchenne muscular dystrophy, another orphan disease he studies, Dr. Flanigan’s research group puts out a monthly podcast to parents and primary care doctors. He’s a fundraiser who writes grants, informs foundations and parents about his work and, when the time is right, asks them to help fund the next step.

Karen McCoy, MD, chief of the Section of Pulmonary Medicine at Nationwide Children’s, also wears many hats while working on a more common orphan disease.

Dr. McCoy is a principal investigator for the Cystic Fibrosis Therapeutic Development Center and the director of the Cystic Fibrosis Center at the hospital. Her work has been funded by the Cystic Fibrosis Foundation for 28 years. In her role as educator, Dr. McCoy limits her trainees to those who will continue in academic medicine.

“There’s still so much to learn,” she says.

The Cystic Fibrosis Foundation is 60 years old, serves 30,000 U.S. patients and has been integral to bringing treatments to market. Like the Sanfilippo foundations, it was started by parents of patients.

“At the beginning of my medical career, I learned about cystic fibrosis and sickle cell disease. Both kill early and make for a very hard life,” Dr. McCoy says. “But sickle cell has not had the benefits of a powerful organization backing research. There have been improvements in care, but not to the degree seen in cystic fibrosis.”

With more patients come more helping hands and more clout. But beyond that, the Cystic Fibrosis Foundation is held up as a model organization. The foundation’s headquarters in Bethesda, Maryland, has developed and maintained strong relationships with the NIH and the Food and Drug Administration — groups the foundation relies on for grant funding and drug approvals.

The foundation created and certifies more than 110 care centers and 82 therapeutic development centers at hospitals across the United States. These provide treatment, advocate for patients and conduct clinical trials. By holding the centers to the same high standards, the centers provide strong, repeatable data needed to bring drugs to market quickly.

“It’s a group effort to make advances,” Dr. McCoy says.

COMMITMENTS TO THE FUTURE

The Cystic Fibrosis Foundation made history this year when it took in $3.3 billion by selling royalty rights to drugs it helped develop. That’s as much money as the organization raises in a decade.

Leaders say the money will be folded back into foundation efforts to allow each successive drug to help fund the next attempt to provide cures. One of the drugs, Kalydeco®, is among the most costly on the market at $300,000 annually, but the results are phenomenal, Dr. McCoy says.

Despite the cost, no insurance company has yet rejected payment for Kalydeco®, and foundation officials say parents aren’t complaining, either. They want cures.

As do the McGees. Reagan, now 3, is part of a foundations-funded study helping doctors learn the natural progression of Sanfilippo syndrome — information needed to measure whether treatments in clinical trials make a difference.

Reagan was recently fitted with hearing aids due to hearing loss.

“We feel like it’s a race against time now,” Peter McGee says. “We want to be in that window where there can be a cure.”

The couple doesn’t dwell on the other possibility.

“Other families whose children have died have kept their foundations going and continue raising money for the cause,” Peter McGee says.

His wife shares his determination. “We’ll continue fighting.”

 

 

References:

McCarty DM, Fu H, inventors; Nationwide Children’s Hospital Inc., assignee. Products and methods for delivery of polynucleotides by adeno-associated virus for lysosomal storage disorders. United States Patent Application US 20130323207 A1. 2013 Dec 5.