April, 2019
 |
| Dr. Lauriel Earley from the University of North Carolina - Chapel Hill, will work on a PANK2 gene therapy for the treatment of PKAN in her newly awarded grant. |
Two new grants to study PKAN were awarded early this year by the NBIA Disorders Association in collaboration with two of our European sister organizations, AISNAF in Italy and Hoffungsbaum e. V. in Germany.
These grants mark the first time all three NBIA groups have teamed up to fund research projects.
The organizations received 12 proposals, with eight focusing on PKAN, three on BPAN and one on MPAN. All were evaluated by an International Scientific Advisory Board made up of scientists and clinicians with expertise in the field of rare, neurodegenerative diseases, including NBIA. In a second step, the projects deemed worthy of funding were shared with a Lay Review Board consisting of parents and patient representatives. The lay group had the final say on which projects would be funded.
The members selected two PKAN studies. No proposals to study BPAN or MPAN met the funding standards, so a new call for proposals for these two disorders went out in March.
Late last year, the lay group chose a proposal from Dr. Lauriel Earley, a postdoctoral fellow from the University of North Carolina – Chapel Hill, to study PKAN. Funding for her project in the amount of 39,500 euros started in February. Another PKAN grant of 22,000 euros will go to Dr. Dario Finazzi, an associate professor of molecular biology, from the University of Brescia in Italy. Funding for his project will begin in May.
Earley is working on a gene therapy to treat PKAN in her project, “PANK2 gene therapy for treatment of PKAN and elucidation of disease biology.” PKAN is caused by mutations in the PANK2 gene and her plan is to deliver a corrected version of PANK2 using a non-disease causing virus to deliver the gene inside the body.
“For decades, work on using adeno-associated virus (AAV) as a tool to treat genetic disease has finally resulted in safe, successful clinical trials that have long-lasting improvement in the lives of many patients,” Earley said. “The first FDA approval and commercialization of an AAV-based gene therapy in the United States occurred in 2018 to treat a genetic disease that causes blindness in children. The concept behind this treatment is simple, but can take many years of work to perfect.”
Viruses like AAV have two main components: a small DNA genome that is protected by an outside protein shell, called a capsid. The capsid acts like a delivery vehicle that is able to enter cells and take the DNA where it needs to go. To turn this into a treatment for disease, the researcher makes this virus in the laboratory and replaces the viral genes with a corrected copy of the needed human gene.
In essence, the virus acts like a beneficial Trojan horse, smuggling the therapeutic gene into patient cells.
“The PANK2 gene is short enough to fit inside the capsid and the area affected by the disease is restricted to the brain and eyes, so only a relatively small amount of virus will be needed,” Earley said. “And we can deliver the therapeutic virus directly to the brain using a safe and minimally invasive surgery.
“The problem in the past with attempting this therapy is that we didn’t have a robust animal model to test it in, but we now have a mouse model we can use to test the safety and efficacy of an AAV-delivered PANK2 gene. In addition, because we can control which types of cells will produce the PANK2 protein, we can determine if specific cell types such as neurons or glial cells are more important in PKAN disease progression than others.”
Her ultimate goal is to halt or prevent disease progression. For the first time, researchers can test to see if simply putting a correct PANK2 sequence into the globus pallidus part of the brain will correct PANK2 deficiency in PKAN-affected mice. She hopes that the information gained from this proposal will generate the necessary data needed before attempting the treatment in humans.
It is a long road to therapy, but the funding provided by AISNAF, Hoffnungsbaum and our organization is the first important step along the path.
Earley will present her work at our family conference.
 |
| Dr. Dario Finazzi from the University of Brescia in Italy, will focus on a zebrafish model in his PKAN research grant. |
In the other funded proposal, Finazzi said he believes his project, “Understanding and curing PKAN: advancements from the phenotypic rescue of a zebrafish model,” can provide a significant contribution to a future cure for PKAN.
Zebrafish embryos have become a favorite drug discovery model because they are compatible with large-scale screening of compounds, he said.
The funding from AISNAF, Hoffungsbaum and NBIA Disorders Association will be instrumental in completing the characterization of the model and defining robust assays to test a library of FDA-approved compounds, he said.
He added that he believes the funding will make his work more competitive for larger government and foundation grants. He also believes this work will encourage the development of zebrafish models for other NBIA disorders, such as CoPAN and MPAN
