by Patricia Wood
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| Dr. Choukri Ben Mamoun, at Yale University, works on PKAN research in hopes of finding a treatment. |
The NBIA Disorders Association, in collaboration with our sister NBIA organizations in Italy (AISNAF) and Germany (Hoffnungsbaum e.V.), funded Dr. Choukri Ben Mamoun’s PKAN research with a $115,000 grant that was recently completed.
The NBIA groups’ research grant to Ben Mamoun at Yale University was titled “A High-Throughput Screen for PKAN Reversing Agents.” The goal was to look for small molecules that might restore normal function in human cells that are deficient in the PANK2 gene, which is impaired in individuals with PKAN. The hope is that such a drug could restore neurological function.
The PANK2 gene encodes the pantothenate kinase enzyme, which is involved in several essential biochemical reactions in the body. A drug that restores normal metabolism in the absence of PANK2 could be effective in treating PKAN.
To identify such compounds, Ben Mamoun’s group developed a tool using luciferase, a glowing enzyme. They connected the instructions for making this glowing enzyme to the “on-off switches” (promoters) of genes involved in producing CoA. This means that when the genes responsible for making CoA are "turned on," the cells will also make luciferase and glow. Measuring this light shows how active the CoA genes are. This system helps researchers understand CoA production and screen for compounds that could correct metabolic problems in PANK2-deficient human cells as well as animal models of the disease.
A large-scale screening of 64,168 compounds from a chemical library at Yale University identified 623 active compounds with potential as PKAN therapeutics. Further validation of these hits will be conducted through additional rounds of screening. These compounds will need to be further characterized to determine whether they act as reversal agents and restore normal metabolic function in PANK2-deficient human cells and in living animals with PKAN-like symptoms. The lab will also need to conduct safety and pharmacological studies in mice and initiate in vivo efficacy studies using PKAN mouse models.
While tangible progress has been made in identifying potential candidates, there is still work to be done in identifying a limited number of molecules to be tested. To do this additional screening, new funding is required.
To keep this important work moving forward, Ben Mamoun is applying for a National Institutes of Health (NIH) grant and seeking other sources of funding. We are hopeful that this exciting research will one day lead to a treatment that improves the lives of individuals living with PKAN.
