The NBIA Disorders Association board is awarding $239,680 to three research projects that received top scores from a pool of 22 grant applications.
After receiving recommendations from grant reviewers with the organization’s Scientific & Medical Advisory Board, the trustees selected projects that scored highly for scientific merit and are expected to lead to greater understanding of four distinct forms of NBIA.
The grants will further research into PLA2G6-Associated Neurodegeneration, an NBIA disorder known as PLAN, Mitochondrial-membrane Protein-Associated Neurodegeneration, or MPAN, Beta-propeller Protein-Associated Neurodegeneration, or BPAN, and a novel, new NBIA gene.
In addition to these grants, the board plans to make a special round of awards to study the most common form of NBIA, Pantothenate Kinase-Associated Neurodegeneration, or PKAN.
A call for applications will be made after the trustees conclude a strategic planning session in late April and confers with our Scientific & Medical Advisory Board on goals for the PKAN studies.
Here are details of the three awards:
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| Drs. Joanne Ng, Ahad Rahim, Manju Kurian and Esther Meyer from the University College London, in London, England, are researchers working on two NBIA grants recently awarded by our organization. |
Our largest-ever grant, $150,000 for a three-year study titled “Novel Therapeutic Strategies in NBIA: A Gene Therapy Approach for PLA2G6-Associated Neurodegeneration (PLAN),” could make a life-changing difference in the lives of those living with PLAN. The awards goes to Dr. Manju Kurian, working with Drs. Ahad Rahim, Joanne Ng and Simon Waddington from University College London and Great Ormond Street Hospital in London, England.
PLAN includes infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy and adult-onset dystonia-parkinsonism. “There are currently no disease-modifying treatments for our patients with PLA2G6-related disease, and developing a new treatment strategy is an absolute priority,” Kurian said.
Her team will use the PLA2G6 mouse model, which is an excellent disease model of PLAN, to develop a gene therapy strategy aiming at curing or significantly improving symptoms in the diseased mice. The team has expertise in gene therapy and will use a “viral vector” as a delivery system to replace the faulty gene with a working gene. That way, the normal PLA2G6 protein is restored to the parts of the body that need it: the brain and the nerve cells. The researchers hope this strategy paves the way for future clinical trials in patients with this form of NBIA.
A requisite for a clinical trial in gene therapy is a detailed understanding of the disease, so the researchers will also undertake natural history studies to understand the clinical course and long term outcomes of those with PLAN.
The research group is part of a wider team at University College London (UCL), which has a track record in bringing such “proof-of-concept” laboratory studies to clinical practice.
A second grant, valued at $44,680 titled “Functional Characterization of Newly Identified NBIA Disorders Using Neuronal Cell Models” also will go to Kurian. She will be working with with Dr. Esther Meyer also at UCL. They plan to study how genetic mutations cause disease in patients with BPAN.
They also will study the genetic mutation that causes disease in a new NBIA subtype that is the topic of a soon-to-be-published gene discovery.
In this project, they will convert patient skin cells into neurons (brain cells) and study these cells. The ultimate aim is to test new drug compounds in the cell model to see if they improve the signs of disease, which, if successful, could lead to the development of new therapies for patients with these NBIA conditions.
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| Drs. Arie Geerlof, Aria Messias, and Arcangela Iuso from the Helmholtz Center Munich, Germany, received a $45,000 grant to study MPAN. Behind them is the NMR spectroscopy machine that they will use in their research. |
Finally a $45,000 grant is going to Dr. Ana Messias, working with Drs. Arie Geerlof and Arcangela Iuso from the Helmholtz Center Munich, Germany, for the project titled “Three-dimensional structure determination and preliminary function analysis of C19orf12, a protein involved in NBIA.”
Messias and Geerlof are structural biology experts and Iuso is part of the team that in 2011 identified the MPAN gene.
Since the identification of the C19orf12 gene, several mutations have been identified as being responsible for MPAN, but how that happens remains a mystery, as the gene has no known similarities with other known genes and its function in the cell is unknown.
This research proposes to unravel the function of the C19orf12 gene by studying the structure of the protein it encodes. They will do this using Nuclear Magnetic Resonance (NMR) spectroscopy, a method based on the same principles as an MRI, which is used in medicine for imaging the human body. X-ray crystallography will also aid in determining the structure of the protein. This method is centered on the diffraction patterns produced by X-rays upon passing through protein crystals, a phenomenon also used to produce holograms on credit cards.
It is hoped that the information gained will allow the researchers to unravel what the C19orf12 protein does in the body using software analysis, which compares it with other known proteins with known function. They will also do biochemical testing of possible functions of the protein in the laboratory to better understand its function.
The goal is to see how mutations lead to disease and, ultimately, uncover possible therapies for patients with MPAN.
