NBIA NEWS & INFORMATION

December 2021

For her deep commitment and enduring service to the NBIA community,  Dr. Susan Hayflick of the Oregon Health & Science University received the “Rare Champion of Hope in Medical Care and Treatment” award from Global Genes. 

This award celebrates medical and health care professionals who have made significant contributions to clinical care and treatment of rare conditions. Hayflick was nominated by the NBIA Disorders Association Board of Trustees in recognition of her 30 years of dedication to the NBIA community. 

Global Genes, a leading rare disease patient advocacy organization, annually recognizes and celebrates inspiring individuals who work to improve the lives of individuals with rare disorders. It presented the 2021 awards at a ceremony in Philadelphia in November, held in-person and virtually.

“Dr. Hayflick is the one constant who has been working on NBIA since before most of

us ever heard of it,” NBIA Disorders Association Vice President Mary Ann Roser said on behalf of the board. “She is a source of hope for all of us — for NBIA individuals, their families, the board members and the entire NBIA community.”

Hayflick thanked the worldwide NBIA community for the award, saying, “you are my family.” She spoke of being driven by hope, calling it her “fuel” and “the glue that holds groups together, whether in a laboratory, or at home or in an advocacy community. …Without hope, there is not a path forward, but with hope, everything is possible.”

For the past 25 years, Hayflick has served as the director of the association’s Scientific & Medical

Advisory Board, in addition to being the premier NBIA researcher, expert and supportive physician-friend to patients and families the world over. Her journey began in Buffalo, New York, in 1991 when she received a call from a neurologist who asked for her opinion on a devastating neurological condition affecting three of the four children of an Amish couple who lived nearby. All three children were ultimately diagnosed with PKAN, one of the most common forms of NBIA. The family’s plight touched Hayflick heart and inspired her to look for the gene responsible for the disease.

She has since worked tirelessly to understand NBIA disorders and develop treatments for affected individuals. She, her team and collaborators around the world have discovered such NBIA genes as PANK2 for PKAN, PLA2G6 for PLAN, FA2H for FAHN and WDR45 for BPAN

At OHSU in Portland, Hayflick is a professor and chair of the Department of Molecular & Medical Genetics. Her lab is working with collaborators on a clinical trial for treating PKAN in which patients can receive the compound being tested, CoA-Z, in their community, without having to travel to Oregon. That innovation may become a model for the rare disease community on how to run a clinical trial in a way that prioritizes convenience for patients and families. Travel to a trial site is a known barrier to clinical trial participation, especially in the rare disease community.

In accepting the Rare Champion of Hope award, Hayflick told the audience to “find hope, foster hope, create hope, be hopeful, as I am.”

December 2021

A Yale University professor has received a research grant worth $115,000 that could help lead to a treatment for PKAN, the second most common form of NBIA.

Choukri Ben Mamoun, Ph.D., at Yale University, receives grant for $115,000 to study PKAN.

Choukri Ben Mamoun, Ph.D., a professor of medicine (infectious diseases) and microbial pathogenesis at Yale, won the “Best Presentation” award in Yale Lifesciences PITCHFEST 2020 for his work on a possible treatment for Pantothenate Kinase-Associated Neurodegeneration (PKAN). That award prompted three NBIA patient organizations—the NBIA Disorders Association, Hoffnungsbaum e.V., in Germany and AISNAF in Italy—to collaborate on making the grant, in August. 

Ben Mamoun also received the Blavatnik Award this year, which is awarded by the Blavatnik Fund for Innovation at Yale University to select projects after a competitive application process. The $300,000 award provides additional seed funding for the PKAN project.

The NBIA groups’ research grant to Ben Mamoun is titled “A High-Throughput Screen for PKAN Reversing Agents.” The goal is to look for small molecules that restore normal function in cells that are deficient in the PANK2 gene, which is impaired in PKAN individuals.

PANK2 directs the production of pantothenate kinase, which is involved in the execution of several essential biochemical reactions in the body. So, a drug that restores or mimics the function of the PANK2 gene could be effective in treating PKAN.

Ben Mamoun will look for small molecules to create a drug that can activate a second Pank enzyme to compensate for the loss of PANK2. The hope is such a drug could restore neurological function in PKAN individuals. The research also will evaluate the safety and efficacy of this novel treatment by conducting tests in the lab and in mouse models.

Previously, Ben Mamoun’s research focused on developing new antimicrobial compounds that do not inhibit human enzymes. Instead, Mamoun’s team discovered that their compounds not only inhibited the human enzyme but that nine of them activated it. That discovery fueled Ben Mamoun’s interest and opened up the possibility to treat PKAN by using the novel compound to activate the gene that causes PKAN.

December 2021

Dr. Young Ah Seo from the University of Michigan School of Public Health in Ann Arbor, Michigan. Work from this grant has been published in the Journal of Neurochemistry.

Dr. Young Ah Seo’s recently completed research, “Defining the Roles of Iron in BPAN,”  has generated new information about how iron accumulates in the brains of individuals with Beta-propeller Protein-associated Neurodegeneration (BPAN), the most common form of NBIA. 

Seo, an assistant professor in the department of nutritional sciences at the University of Michigan School of Public Health in Ann Arbor, and her team, observed that the dysfunctional WDR45 gene in BPAN led to impaired iron storage in the brain, causing iron to build up to a toxic level that damages cells.

In 2018, Seo received the first-ever early-career research grant from the NBIA Disorders Association, for $150,000. Although the grant work was meant to be completed in two years, Seo received a one year, no-cost extension because of delays caused by the pandemic.

Her team’s goal was to identify the major proteins and pathways involved in iron accumulation when the WDR45 gene is deficient and how the altered iron uptake and metabolism contribute to neurodegeneration.

The WDR45 gene is involved in autophagy, a natural process that helps clear unnecessary materials from cells. Exactly how the mutated gene also leads to iron accumulation in the brain has not yet been fully understood, so Seo and her team sought to unravel the mystery.

They successfully generated a cell model of BPAN in which the WDR45 gene was deleted. They saw significantly elevated iron levels in this model, suggesting that it accurately mimicked the condition seen in individuals with BPAN.

They found that the absence of the gene’s protein, also named WDR45 (when not italicized it refers to the protein), led to significant changes in the pathways that are responsible for the uptake and regulation of iron in cells. This may be the basis of brain iron accumulation.

They also observed that the overload of iron in cells in this model was associated with impaired ferritinophagy. This is a form of autophagy that degrades a protein responsible for iron storage in cells, called ferritin. Essentially, the process that helps prevent excessive iron storage was impaired.

Finally, they observed that WDR45 deficiency led to excessive iron accumulation in the mitochondria, altered mitochondria metabolism and overproduction of toxic reactive oxygen species (unstable molecules that easily react and cause cell damage). This may contribute to the neurodegeneration seen with BPAN.

All together, these findings suggest a potential underlying cause of disease to explain how iron accumulates in BPAN. 

Seo’s work from this grant has been published in the Journal of Neurochemistry, titled “A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation”. She intends to seek new funding to expand on the project’s findings.