Raphael Schiffmann M.D.

Hughes, D. A., K. Nicholls, S. P. Shankar, G. Sunder-Plassmann, D. Koeller, K. Nedd, G. Vockley, T. Hamazaki, R. Lachmann, T. Ohashi, I. Olivotto, N. Sakai, P. Deegan, D. Dimmock, F. Eyskens, D. P. Germain, O. Goker-Alpan, E. Hachulla, A. Jovanovic, C. M. Lourenco, I. Narita, M. Thomas, W. R. Wilcox, D. G. Bichet, R. Schiffmann, E. Ludington, C. Viereck, J. Kirk, J. Yu, F. Johnson, P. Boudes, E. R. Benjamin, D. J. Lockhart, C. Barlow, N. Skuban, J. P. Castelli, J. Barth and U. Feldt-Rasmussen (2016). “Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in fabry disease: 18-month results from the randomised phase iii attract study.” J Med Genet: 2016 Nov [Epub ahead of print].

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BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in alpha-galactosidase (alpha-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of alpha-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of alpha-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.

Desnick, R. J., N. W. Barton, S. Furbish, G. A. Grabowski, S. Karlsson, E. H. Kolodny, J. A. Medin, G. J. Murray, P. K. Mistry, M. C. Patterson, R. Schiffmann and N. J. Weinreb (2016). “Roscoe owen brady, md: Remembrances of co-investigators and colleagues.” Mol Genet Metab: 2016 Nov [Epub ahead of print].

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To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady’s research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady’s efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady’s pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases.

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics 47(6): 349-354.

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Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Zhong, X. Z., X. Sun, Q. Cao, G. Dong, R. Schiffmann and X. P. Dong (2016). “Bk channel agonist represents a potential therapeutic approach for lysosomal storage diseases.” Sci Rep 16(1): 503.

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Efficient lysosomal Ca2+ release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca2+-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca2+ release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca2+ release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs. In this study, we assessed the effect of BK agonist, NS1619 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-F408), Niemann-Pick type A (NPA) and Fabry disease. We found that TRPML1-mediated Ca2+ release was compromised in these LSDs. BK activation corrected the impaired Ca2+ release in these LSDs and successfully rescued the abnormal lysosomal storage of these diseases by promoting TRPML1-mediated lysosomal exocytosis. Our study suggests that BK channel activation stimulates the TRPML1-BK positive reinforcing loop to correct abnormal lysosomal storage in LSDs. Drugs targeting BK channel represent a potential therapeutic approach for LSDs.

Benjamin, E. R., M. C. Della Valle, X. Wu, E. Katz, F. Pruthi, S. Bond, B. Bronfin, H. Williams, J. Yu, D. G. Bichet, D. P. Germain, R. Giugliani, D. Hughes, R. Schiffmann, W. R. Wilcox, R. J. Desnick, J. Kirk, J. Barth, C. Barlow, K. J. Valenzano, J. Castelli and D. J. Lockhart (2016). “The validation of pharmacogenetics for the identification of fabry patients to be treated with migalastat.” Genet Med: 2016 Sep [Epub ahead of print].

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PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of alpha-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the alpha-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in alpha-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell alpha-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (>/=0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.