|Contact | Education | Interests | Activities | Leadership | Publications|
- M.D., Universidade Federal do Parana Medical School, Curitiba, Brazil, 2000
- Pediatrics/Medical Genetics Residency, Hospital de Clinicas de Porto Alegre, Brazil, 2003
- Clinical Genetics Fellowship, The Hospital for Sick Children, Toronto, ON, Canada, 2005
- Clinical and Research Fellowship, Inherited Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada, 2008
- Ph.D., Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, 2008
The research in my lab is focus 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 accumulation of undigested, or partially digested intermediates. The LSDs (nearly 60 types) are individually rare genetic conditions, but, collectively, the incidence is approximately 1/7,000 live births. Interestingly, the development of clinical symptoms in patients is neurologically progressive, and usually correlates with a level of residual deficient enzyme activity. In most cases, the observed residual lysosomal activity is a result of missense mutations, which partially preserves catalytic enzyme function but mostly impairs the early folding process in the ER. These mutant lysosomal enzymes do not reach its appropriate conformation, and subsequently are directed to ER-associate degradation (ERAD) pathway, and are ultimately degraded by the ubiquitin-proteosome system. In this context, small molecule therapeutics are an attractive approach to treat LSDs. Enzyme-enhancement agents including pharmacological chaperones (PC) are small molecules which are able to assist a mutant misfolded protein to achieve a native-like conformation in the endoplasmic reticulum (ER), allowing it to escape the ERAD pathway, and reach the lysosome. In my 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 glucocebrosidase, enzyme deficient in Gaucher disease (Maegawa et. al. 2009). These molecules can be identified by high- and medium-throughput screening of selected libraries of drug-like compounds. An advantage of this approach is that small molecules (<500 Da) are much more likely to cross the blood brain barrier and reach neuronal cells, which are dramatically affected in LSDs. In addition, principles learned in treating one type of LSD can be applied not only to other LSDs, but also to other misconformation protein diseases, which is also feature of common neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease.
We are currently developing high throughput screening (HTS) assays to identify specific chemical compounds to assist folding of mutant lysosomal proteins. The HTS is based on live-cell assay, which, if appropriate designed, will not only identify potential therapeutic compounds, but also to assist in dissecting molecular mechanism of the pathogenesis misconformation protein diseases, most of them still unclear in several genetic diseases such as LSDs. The advantage of the live-cell HTS is that the protein of interest is evaluated in the context of an intact cell, which is crucial in transmembrane proteins, or proteins that function in a multi-component complex. In addition, the live-cell HTS for different lysosomal disease-causing proteins will generate candidates compounds that may be enhancing the general protein-folding cell capacity by other mechanism than the physical interaction with the specific the protein of interest.
- Development of treatment strategies for lysosomal storage diseases on pre-clinical and clinical level
- Molecular pathogenesis of lysosomal storage diseases
- Molecular mechanism and manipulation of protein folding
- Understanding the regulation of the posttranslational endoplasmic reticulum quality control system
- Board Certifications:
- American Board of Medical Genetics, Clinical Genetics, 2005
- Canadian College of Medical Genetics, Fellow in Clinical Genetics, 2006
- American Board of Medical Genetics, Clinical Biochemical Genetics, 2007
Clinic: Johns Hopkins Harriet-Lane Outpatient Clinic
Attending, clinical metabolic and genetics consultation service
- Faculty, Johns Hopkins University Medical Genetics Residency and Clinical Genetics Fellowship Programs
Exceptional Trainee Award – Genetics & Genomic Biology Program – The Hospital for Sick Children Research Institute Retreat. Toronto, ON, Canada. November, 2007.
Maegawa GHB, Tropak M, Buttner JD, Rigat B, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JTR, Mahuran DJ. Identification and characterization of ambroxol as an enzyme-enhancement agent for Gaucher disease. J Biol Chem 2009 Aug 28;284(35):23502-16.
Maegawa GHB, Banwell B, Blaser S, Hawkins C, Arckerley C, Hayes J, Tlopak M, Sorge G, Clarke JTR. Substrate reduction therapy in juvenile GM2 gangliosidosis. Mol Genet Metab 2009 Sep-Oct;98(1-2):215-24
Maegawa GHB, Giersbergen PV, Yang S, Banwell B, Morgan CP, Tifft C, Clarke JTR. Pharmacokinetics, tolerability and safety of miglustat as treatment of GM2 gangliosidosis. Mol Genet Metab 2009 Aug;97(4):284-91.
Rohrbach M, Chitayat D, Maegawa G, Shanske S, Davidzon G, Chong K, Clarke JT, Toi A, Tarnopolsky M, Robinson B, Blaser S. Intracerebral periventricular pseudocysts in a fetus with mitochondrial depletion syndrome: an association or coincidence. Fetal Diagn Ther 2009 Mar 25;25(2):177-182.
Tropak, MB, Kornhaber, GJ, Rigat,BA, Maegawa GHB, Buttner J, Blanchard JE, Murphy C, Tuske SJ, Coales SJ, Hamuro Y, Brown E, Mahuran DJ. Identification of pharmacological chaperones for Gaucher disease nd characterization of their effects on b-glucocerebrosidase by hydrogen/deuterium exchange mass spectrometry. ChemBioChem 2008 (9), 2650-2662.
Kornhaber GJ, Tropak MB, Maegawa GHB, Tuske SJ, Coales SJ, Mahuran DJ, Hamuro Y. Isofagomine Induced Stabilization of Glucocerebrosidase” ChemBioChem 2008 (9), 2643-2649.
Maegawa GHB, Poplawski N, Andresen BS, Olpin SE, Nie G, Clarke JTR, Teshima I. Interstitial Deletion of 1p22.2p31.1 and Medium-Chain Acyl-CoA Dehydrogenase Deficiency in a Patient with Developmental Delay. Am J Med Genet (Part A) 2008 Jun 15;146A(12):1581-6.
Maegawa GH, Tropak M, Butner J, Stockley T, Kok F, Clarke JTR, Mahuran DJ. Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem. 2007, 82(12): 9150-9161.
Maegawa GHB, Stockley T, Tropak M, Kok F, Giugliani R, Mahuran D, Clarke JTR. The natural history of juvenile or subacute GM2 gangliosidosis: 21 unreported cases and literature review of 134 cases. Pediatrics 2006, Oct 2; e1550-1562.
Maegawa GHB, Chitayat D, Blaser S, Whyte H, Thomas M, Kim P, Kim J, Taylor G, McNamara P. Bilateral microtia with absence of external auditory meati, fused ossicles and Mondini dysplasia, duodenal atresia, anal anomalies, thyroid hemiaplasia and biliary atresia. A new mandibulofacial dysostosis syndrome? Clin Dysmorph 2006, 15: 191-196.
Gustavo H.B. Maegawa, MD, PhD
McKusick-Nathans Institute of Genetic Medicine
733 N. Broadway, Room 409
Baltimore, MD 21205
Phone: (443) 287-3505
Fax: (410) 502-5677