NBIA NEWS & INFORMATION

Professor Robin Ketteler of University College London research update. Funds for the research grant were raised at the 2018 Million Dollar Bike Ride.

October 2020

Professor Robin Ketteler and his team at University College London have completed drug screening for potential BPAN therapies and identified several candidates that will advance to the next level of testing.

Ketteler’s team received a 2019 grant from the NBIA Disorders Association and recently reported the successful results. The BPAN drug-candidates can restore autophagy in BPAN cells, the natural process of cleaning up toxic damage in cells that is impaired in BPAN patients.

“Our results are a great starting point for further drug development,” says Ketteler. “These chemicals have characteristics of drugs, and they work in our neuronal cell model.”

The next steps are to ensure that these drug-like molecules also work in the more complex environment of the brain and can reach the brain regions that most need help.

To that end, the team plans to develop tissue models of BPAN using three-dimensional cell models.

Ketteler’s grant was made possible from funds raised by BPAN families for the 2018 Million Dollar Bike Ride held by the Orphan Disease Center at the University of Pennsylvania. Our organization writes the request for proposals and members of our Scientific & Medical Advisory Board review the applications. The University of Pennsylvania manages the grants and sends us copies of the scientific reports that are generated.

This work was done in collaboration with Professor Manju Kurian and Dr. Apostolos Papandreou, both from University College London. They had received a grant to study BPAN from our organization in 2014. (See article at https://www.nbiadisorders.org/images/newsletters/2018-apr-may-news.pdf, pg. 6).

Ketteler’s team built on the 2014 work, which produced a laboratory model of BPAN, using skin cells from BPAN patients and reprogramming those cells into neurons. Those cells were examined using state-of-the-art techniques to identify differences from cells in healthy people. The researchers learned that genes and proteins involved in iron metabolism are present in the patients’ cells at abnormal levels in comparison to healthy cells. This is in line with the disease’s characteristic buildup of iron in the brain. This finding encouraged the team to look more closely at the potential causes for such an increase in iron.

Ketteler is an expert in early stage drug discovery. “These findings are very exciting,” he said. “They present an opportunity to use our drug screening technologies to identify small molecule chemical compounds that might restore autophagy in these cells.”

Using innovative screening technologies involving sound to propel compounds onto the cells, Ketteler screened thousands of small molecule compounds for ones that might enhance autophagy in BPAN neurons. Interestingly, some of the compounds are part of a collection of FDA-approved drugs already being used for other diseases.

Ketteler is seeking additional funding to continue this research.

June 2020

Team NBIA did it again! For the fourth consecutive year, the NBIA Disorders Association successfully met the goal set by the Million Dollar Bike Ride and will have $30,000 matched, dollar for dollar, by the University of Pennsylvania’s Orphan Disease Center.

The team’s efforts will result in a $60,000 grant for BPAN research to be awarded later this year. BPAN, which stands for Beta-propeller protein-associated neurodegeneration, has emerged as the most common NBIA disorder. The Million Dollar Bike Ride has been a big source of support for BPAN research, a priority of the NBIA Disorders Association, bringing in $130,000 in matching money alone from UPenn over the past three years. With this match, the BPAN grants will exceed $320,000.

Despite a global pandemic, the 7th Annual Million Dollar Bike Ride carried on. Virtually, of course. Originally set to take place in Philadelphia on June 13, this year’s ride was held in communities around the world to help rare disorders while maintaining social distancing amid COVID-19.

Steve and Kristi Florio from Boalsburg, PA rode their bikes at Penn State University as part of the virtual MDBR. Their daughter Lia has BPAN and enjoyed riding along with her father.

In all, 712 cyclists from 39 states, Germany, Canada and Australia pledged to ride 20,567 miles for a variety of rare disorders. Virtual riders could participate with a bike ride in their neighborhoods or on stationary bikes raising funds until June 30.

Our team had 26 cyclists and 10 families that created fundraising pages in addition to our main Team NBIA Disorders page. A shout out to Roselle and Jeff Guzman of Alexandria, Virginia, who jumped in and raised $10,581 in less than two weeks! Their daughter, Salia-Rose, was recently diagnosed with BPAN.

Our sister organization, Hoffnungsbaum e.V., led by Markus Nielbock, also created a fundraising page so that BPAN families in Germany could participate; they raised $2,500

For six weeks starting in May, MDBR organizers held challenges each week to keep interest high and encourage participation. The Ftikas family of Cranbury, N.J., whose daughter Lexi Fae has BPAN, won week three, which was a fundraising challenge, by raising $1,940, the most funds raised from any team that week. On June 13 there was a thank-you presentation for all MDBR teams followed by a virtual spin class for registered riders where many did their pledged miles. Team NBIA Disorders had six cyclists participating in the class, while others took to their neighborhoods to ride that day.

Matt Ritzman and his daughter Josie who has PLAN participate in the virtual 2020 Million Dollar Bike Ride and raise $1550 for BPAN research.

Avid cyclist and NBIA board Chair Matt Ritzman of Oakland, California, said he had always wanted to take part in the ride and was thrilled to do so this year with his wife, Julie, and daughter, Josie, who has NBIA.

“I planned our ride,” he said recently. “There’s a 27-mile loop near my house that’s absolutely beautiful. It’s not easy; there are lots of hills and I was carrying Josie (on a tandem bike). But she’s a fun passenger to have aboard. She loves the wind blowing in her face, and she talks a lot when we’re out. I think it’s one of her favorite activities.”

The amount raised each year “is truly remarkable considering how rare this disorder is,” Ritzman said. “I think it can be attributed to how much we support each other. My daughter has PLAN, not BPAN, so she won’t be directly impacted by the research, but I feel just as much joy when we make progress with any of these disorders.”

2020 MDBR Video

June 2020

Thanks to money raised in last year’s Million Dollar Bike Ride, the NBIA Disorders Association is supporting a stem cell research project in Australia that will examine BPAN’s effects on the brain and drugs that could help treat the disorder.

Dr. Paul Lockhart of Murdoch Children’s Research Institute (MCRI) in Melbourne is leading the project and received a grant in February for $60,561 from the bike ride’s sponsoring organization, the University of Pennsylvania. Of that total, the NBIA community raised $30,561 and won the maximum match of $30,000 from the school’s Orphan Disease Center to study Beta-propeller Protein-Associated Neurodegeneration (BPAN).

Our organization was deeply involved in the grant-making process. We wrote the request for proposals, and members of our Scientific & Medical Advisory Board reviewed the applications and made recommendations. The University of Pennsylvania will manage the grant and send us a copy of the final scientific report that Lockhart’s team submits.

The project is titled “Development of novel human stem cell models of BPAN for disease modeling and drug screening,” and is being conducted by the Bruce Lefroy Centre, a genetics research unit at MCRI, where Lockhart is co-director. His co-investigators are Dr. Martin Delatycki and Dr. Jay Shukla.

BPAN families in Australia meet with researchers at the Murdoch Children’s Institute in Melbourne.

The team has identified 11 individuals in Australia who have BPAN, ranging in age from toddlers to a 36-year-old. Most of them have agreed to donate their skin cells for the study. MCRI researchers will reprogram those cells using cutting-edge stem cell technologies to generate the kind of nerve cells affected by BPAN. This ‘brain in a dish’ model allows direct testing of how BPAN affects brain function and offers a way to rapidly screen large numbers of drugs for potential treatments.

The team will create neural networks that mimics the way nerve cells communicate with each other in the human brain. They hope these models will help them identify what causes specific neurons in the brain of BPAN-affected individuals to degenerate much earlier than in individuals without the disorder. In addition, the team will use the models to test drug compounds that might be effective in treating BPAN. Such studies are required before a potential treatment can move to a clinical trial in patients.

This research is part of a larger project launched in December 2019 with an anonymous $200,000 donation in honor of five-year old Angus Hunter, who has BPAN. The Hunter family lives in Melbourne and is active in raising awareness and funds for BPAN research, as well as providing support to BPAN families.