Abstract-Background:Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid ␣-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. Methods: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n ϭ 9) or 40 mg/kg (n ϭ 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. Results: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. Conclusions: Recombinant human acid ␣-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid ␣-glucosidase in which patients were older.

Globotriaosylceramide accumulation in the Fabry kidney is ance was more limited than that observed in other cell types. cleared from multiple cell types after enzyme replacement therapy.No evidence of immune complex disease was found by immuno-Background. Fabry disease, a lysosomal storage disease caused fluorescence despite circulating anti-r-h␣GalA IgG antibodies. by deficient lysosomal ␣-galactosidase A activity, is character-Conclusions. These findings indicate a striking reversal of ized by globotriaosylceramide (GL-3) accumulation in multiple renal glycosphingolipid accumulation in the vasculature and in cell types, particularly the vasculature, leading to end organ other renal cell types, and suggest that long-term treatment failure. Accumulation in the kidney is responsible for progreswith r-h␣GalA may halt the progression of pathology and sive decline in renal function in male patients with the classical prevent renal failure in patients with Fabry disease. phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the Fabry disease is an X-linked recessive disorder in which only available treatment options for end-stage renal disease.affected males are deficient in the lysosomal enzyme Methods. The pre-and post-treatment renal biopsies were ␣-galactosidase A. This deficiency leads to accumulation analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by

GATA-family transcription factors are critical to the development of diverse tissues. In particular, GATA-4 has been implicated in formation of the vertebrate heart. As the mouse Gata-4 knock-out is early embryonic lethal because of a defect in ventral morphogenesis, the in vivo function of this factor in heart development remains unresolved. To search for a requirement for Gata4 in heart development, we created mice harboring a single amino acid replacement in GATA-4 that impairs its physical interaction with its presumptive cardiac cofactor FOG-2. Gata4ki/ki mice die just after embryonic day (E) 12.5 exhibiting features in common with Fog2 −/− embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventricle. These findings establish an intrinsic requirement for GATA-4 in heart development. We also infer that GATA-4 function is dependent on interaction with FOG-2 and, very likely, an additional FOG protein for distinct aspects of heart formation. Transcriptional activity of the GATA-factors is modulated through interaction with nuclear proteins, including zinc finger proteins of the Kruppel and FOG/Ushaped families, general coactivators (p300 and CBP), the myocardial-expressed protein Nkx2.5, and NF-AT3 (Durocher and Nemer 1998;Mackay and Crossley 1998;Blobel 2000;Molkentin 2000). Whereas the specificity and in vivo functional relevance of many of these interactions are incompletely defined, the association of GATA-1 with FOG-1 has been examined in detail. FOG-1 interacts with GATA-1 in hematopoietic cells and regulates the ability of GATA-1 to promote terminal differentiation of erythroid cells and megakaryocytes (Tsang et al. 1997). Mutation of specific residues within the conserved N-terminal zinc finger of GATA-1, such as V205G, disrupts binding to FOG-1, preserves DNA-binding properties of GATA-1, and renders GATA-1 unable to promote terminal differentiation of red blood cells (Crispino et al. 1999). Furthermore, mutation of Val 205 in humans leads to congenital dyserythropoietic anemia and thrombocytopenia (Nichols et al. 2000). Taken together, these findings demonstrate that direct physical association of GATA-1 and FOG-1 is essential for GATA-1's roles in transcription and, critical for the experiments reported herein, identifies a specific residue of the N finger that mediates cofactor interaction.GATA-4, GATA-5, and GATA-6, nonhematopoietic expressed factors, are implicated in development of heart, endoderm, and intestinal epithelia, where they are expressed in an overlapping and dynamic fashion Bossard and Zaret 1998;Gao et al. 1998;Koutsourakis et al. 1999;Parmacek and Leiden 1999;Molkentin 2000). GATA-4 has been extensively studied in the context of heart development, as it is present in precardiac splanchnic mesoderm and binds to and activates promoters and enhancers of numerous myocardial-expressed genes . In its absence, mouse embryos die by E7.0-9.5, with failure of ventral morphogenesis leading to cardiac bifida (Kuo et al. 1997;Molkentin et al. 1997). The deat...

Objective-To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid α-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study design-We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echo-cardiograms, growth, and motor and cognitive function.Result-After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. Patients with infantile-onset Pompe disease typically present before 12 months of age with progressive, hypertrophic cardiomyopathy that may obstruct left ventricular outflow; profound muscle weakness and hypotonia; non-attainment or loss of motor milestones; difficulty feeding; and failure to thrive. These patients have a dramatically shortened life span. In patients who are not treated, the median age of death ranges from 6.0 to 8.7 months. 4,7 In the most rapidly progressive form, also termed "classic" infantile Pompe disease, the mortality rate is as high as 92% to 95% in the first year of life. 7 In an historical cohort of patients manifesting Pompe disease in the first year of life, irrespective of phenotype, 74% died by 1 year of age, 91% by 2 years of age, and 93% by 3 years of age. 7 Death generally results from cardiac and respiratory failure. 1,3,7No approved specific treatment for Pompe disease currently exists. However, recombinant human GAA (rhGAA) has shown physiological activity both in animal disease models and in early clinical trials. 8-15 In 3 pilot studies in severely affected infants, rhGAA (purified from transgenic rabbit milk 11-14 or from Chinese hamster ovary [CHO] cell cultures 8 ) markedly ameliorated cardiomyopathy and prolonged all patients' survival beyond 1 year. One of 6 patients given rhGAA from rabbit milk (a preparation that is no longer available) and 1 of 3 patients given CHO cell-derived rhGAA walked independently and remained ventilator-free. The remaining 7 patients from these 3 studies showed lesser degrees of motor improvement and eventually required ventilation. As of January 2006, 3 of the 9 patients in these pilot studies had died and 6 remained alive (unpublished data)...