Two new grants awarded to BPAN researchers in January

April 2019

Two new BPAN grants were awarded in January from the University of Pennsylvania, with crucial input from the NBIA Disorders Association.

In both cases, the grants will enable researchers to build on their previous studies of BPAN, or Beta-Propeller Associated Neurodegeneration, which is fast becoming one of the most common forms of NBIA.

The money for the grants comes from last year’s Million Dollar Bike Ride held in May 2018 by the Orphan Disease Center at the University of Pennsylvania. For the second year in a row, BPAN family supporters rode and managed to qualify for a matching grant of $50,000 from UPenn. Because the riders raised slightly more than the required match, one-year grants of $51,020 each were awarded for the two new BPAN studies.

Our organization writes the request for proposals, and members of our Scientific & Medical Advisory Board review grant applications. The University of Pennsylvania manages the grants, and sends us copies of the scientific reports that grant recipients provide.

Hong Zhang
Dr. Hong Zhang of the Chinese Academy of Sciences in Beijing, has received a $51,020 grant for BPAN research. He is currently a visiting professor at the University of Massachusetts Medical School.

One new grant will go to Dr. Hong Zhang, who received a grant from the 2017 Million Dollar Bike Ride. Zhang will be able to continue his studies into the functions of the mutated WDR45 gene, which causes BPAN. Zhang, a visiting professor at the University of Massachusetts Medical School and a researcher at the Institute of Biophysics, Chinese Academy of Sciences, in Beijing titled his newest project, “Mechanistic study of WDR45/45B and their binding partner ATG2 in the autophagy pathway of neural cells.”

What that means is Zhang will be studying the role of the protein WDR45 that’s made by the WDR45 gene that causes BPAN. He also will study WDR45B, the protein for the WDR45B gene that causes another neurodevelopmental syndrome characterized by intellectual disability, spastic quadriplegia, epilepsy and cerebral hypoplasia. Specifically, he’ll be looking at the impact these proteins have in the neural pathway for autophagy, the natural, multi-step process by which the body recycles or cleans out certain toxic materials to maintain proper functioning and stability.

WDR45 is a mammalian protein (the gene name is italicized while the protein is not) that shares extensive similarity in its protein sequences with WDR45B. When lower case, the gene refers to the animal form.

BPAN is characterized by developmental disabilities in early childhood, with later-onset parkinsonism and cognitive decline in adulthood. Studying autophagy may give clues about what causes the cell damage in BPAN.

Zhang’s grant award in 2017, using nematode worms as a model system to study autophagy, found that the worms have an essential autophagy gene similar in origin to WDR45 and WDR45B.

His lab also showed that when the Wdr45 mice gene is turned off (knocked out) , they had problems with learning and memory, as well as nerve fiber degeneration and autophagy defects, reflecting key features of BPAN.

Zhang’s lab also engineered mice in which both the Wdr45 and Wdr45b genes were turned off. Those mice died within six to eight hours of birth, and the autophagy defects were more dramatic than in mice engineered with either the Wdr45 or Wdr45b inactivated gene.

This work provided the first evidence of the critical function of WDR45B in the autophagy pathway, causing more damage than when WDR45 is not working properly.

Zhang’s 2017 grant award resulted in two papers, one published in December in the Journal of Cell Biology and the other due out soon.

With the new grant, Zhang’s lab will investigate the specific steps at which the WDR45 and WDR45B proteins malfunction in the neural autophagy pathway. The role of WDR45-binding partner ATG2 in autophagy will also be investigated.

“These studies will help us to understand how neural functions are affected in BPAN patients,” Zhang said.

His work is expected to expand the understanding of the cause and progression of the disease and provide more insights into approaches for treating BPAN patients.

Robin Ketteler
Dr. Robin Ketteler at the MRC Laboratory for Molecular Cell Biology at University College London received a $51,020 grant for BPAN research.

Our other grant recipient is Dr. Robin Ketteler at the MRC Laboratory for Molecular Cell Biology at University College London. He is collaborating with the Institute of Child Health, also at UCL, where Dr. Apostolos Papandreou, who works in the lab of Dr. Manju Kurian, did research on a 2014 grant from our organization. Papandreou will be working with Ketteler to build on the 2014 research.

“With this support, we are starting a novel and innovative project to develop strategies for therapeutic modulation of the disease,“ Ketteler said, adding that he’s grateful to families and donors of the Million Dollar Bike Ride for the support.

His project aims to understand the underlying problem that occurs in the brain cells to cause BPAN. Next, the team will use advanced drug screening technologies to start the search for a potential drug to treat BPAN.

They hope the screening will help them identify small chemical molecules that will return the brain cells to a healthier state. “What is most exciting about this work is that the work starts with precious skin biopsies from the patients themselves, placing them at the center of our research,” Ketteler said.

In the previous work done in Kurian’s lab (see April/May 2018 newsletter at https://www.nbiadisorders.org/news-events/nbia-newsletters), a disease model was developed for BPAN based on taking patients’ skin cells and making them into more specialized brain cells.

Ketteler’s lab also is interested in autophagy of brain cells in BPAN individuals. The lab has extensive experience in establishing autophagy assays for screening large collections of small chemical compounds. It uses cutting-edge robotic equipment, including fully automated microscopes that capture hundreds of thousands of images within a day.

The lab also uses sound waves to dispense chemicals onto cells. Researchers treat cells by literally shooting microscopic amounts of chemicals onto them. The lab has a collection of chemicals in its freezers to test with the patient-derived brain cells.

One set of compounds is a collection of FDA-approved drugs that are already in use for other diseases. Using those tried and tested compounds allows a potentially quicker path to a treatment.

“In addition, my lab has recently identified chemicals that specifically modulate autophagy, which is a unique set of compounds that is only available to us. We will monitor cell health, as well as their response to stresses and autophagy,” Ketteler said.

He believes that by identifying those chemicals, his lab is in a strong position to attract further funding from the UK Research Councils or pharmaceutical industry to move these compounds into the clinic.