The research in Dr. Maegawa’s lab is focused on developing new therapies of lysosomal storage diseases (LSDs). These inherited metabolic conditions are caused by defects in a wide spectrum of lysosomal and a few non-lysosomal proteins, resulting in the accumulation of undigested or partially digested intermediates. Small molecule therapeutics are an attractive approach to treat LSDs. Enzyme-enhancement agents, including pharmacological chaperones (PC), are small molecules that are able to assist a mutant misfolded protein to achieve a native-like conformation in the endoplasmic reticulum (ER), allowing it to escape the ER-associated degradation (ERAD) pathway and reach the lysosome.
In Dr. Maegawa’s early studies screening an FDA-approved drug library, pyrimethamine, a drug used to treat malaria and toxoplasmosis, was identified as a PC for hexosaminidase A, which is deficient in GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) (Maegawa et al. 2007). In another study, ambroxol, a drug used for chronic bronchitis, was found to enhance and stabilize mutant forms of glucocebrosidase, an enzyme deficient in Gaucher disease (Maegawa et. al. 2009).
Currently, the lab is developing high throughput screening (HTS) assays to identify specific chemical compounds to assist folding of mutant lysosomal proteins.
Dr. Maegawa’s lab is focused on developing new therapies for lysosomal storage diseases (LSDs) based on the understanding of molecular mechanisms of the pathogenesis of these diseases.
Ongoing research projects are related to:
- Identifying small molecule therapies by HTS assays using LSD patient cells
- Investigating pathogenic cascades in LSDs as potential therapeutic targets
- LSD clinical studies
A Phase 1/2, Open Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Exploratory Efficacy Parameters of PRX-102 Administered by Intravenous Infusion Every 2 Weeks for 12 Weeks to Adult Fabry Patients
Kano SI, Yuan M, Cardarelli RA, Maegawa G, Horiuchi Y, Higurashi N, Gaval-Cruz M, Wilson AM, Tristan C, Kondo MA, Chen Y, Koga M, Obie C, Ishizuka K, Seshadri S, Srivastava R, Kato TA, Sedlak TW, Lee Y, Rapoport JL, Hirose S, Okano H, Valle D, O'Donnell P, Sawa A, Kai M. "Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy." Curr Mol Med. 2015 Mar 2. [Epub ahead of print
Teixeira CA, Miranda CO, Sousa VF, Santos TE, Malheiro AR, Solomon M, Maegawa GH, Brites P, Sousa MM. "Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease." Neurobiol Dis. 2014 Jun;66:92-103. doi: 10.1016/j.nbd.2014.02.012. Epub 2014 Mar 6.
Alqahtani E, Huisman TA, Boltshauser E, Scheer I, Güngör T, Tekes A, Maegawa GH, Poretti A. "Mucopolysaccharidoses type I and II: new neuroimaging findings in the cerebellum." Eur J Paediatr Neurol. 2014 Mar;18(2):211-7. doi: 10.1016/j.ejpn.2013.11.014. Epub 2013 Dec 31.
Pastores GM, Maegawa GH. "Clinical neurogenetics: neuropathic lysosomal storage disorders." Neurol Clin. 2013 Nov;31(4):1051-71. doi: 10.1016/j.ncl.2013.04.007. Review.
Ribbens JJ, Moser AB, Hubbard WC, Bongarzone ER, Maegawa GH. "Characterization and application of a disease-cell model for a neurodegenerative lysosomal disease." Mol Genet Metab. 2014 Feb;111(2):172-83. doi: 10.1016/j.ymgme.2013.09.011. Epub 2013 Sep 21.