Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

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We report the use of the alkaline-earth (Ae) metalcatalyzed dehydrocoupling of silanes and amines for the synthesis of ferrocene-containing polycarbosilazanes. The barium complex [Ba(N(SiMe 3 ) 2 ) 2 •(THF) 2 ] catalyzed the dehydrocoupling of the hydrosilane FeCp(CpSiPhH 2 ) (1) with 1,4-(H 2 NCH 2 ) 2 C 6 H 4 under mild conditions to give a polycarbosilazane with pendant ferrocene groups. The polymer could be readily cross-linked by the addition of phenylsilane to the unquenched reaction mixture. Welldefined polycarbosilazanes with ferrocene in the main chain were also obtained from the dehydrocoupling of hydrosilanes Fe(Cp-(SiPhH 2 )) 2 (3) and Fe(Cp(SiMe 2 H)) 2 (IX) with 1,4-(H(Me)-NCH 2 ) 2 C 6 H 4 and 1,4-(H 2 NCH 2 ) 2 C 6 H 4 , respectively. Crystalline monomeric analogues, FeCp(Cp(SiPh(NHBn) 2 )) (2, Bn = CH 2 (C 6 H 5 )), and Fe(Cp(SiPh(NHBn) 2 )) 2 (4), were also obtained via the dehydrocoupling benzylamine with 1 and 3, respectively. The barium-catalyzed dehydrocoupling of diaminoferrocene with Ph 2 SiH 2 or Ph(Rc)SiH 2 (6, Rc = (C 5 H 4 )Ru(C 5 H 5 )) did not result in polymer, but instead in the formation of the silazanebridged ansa-[3]ferrocenophanes (Fe(η-C 5 H 4 NH) 2 SiPh 2 ) (5) and (Fe(η-C 5 H 4 NH) 2 SiPh(Rc)) (7), respectively. Both polymeric and molecular products were electrochemically investigated, and the polymers proved to be promising precursors to magnetic iron-containing ceramics in yields of up to 64%.

Niemann–Pick type C disease (NP-C) is a fatal neurodegenerative lysosomal storage disorder. It is caused in 95% of cases by a mutation in the NPC1 gene that encodes NPC1, an integral transmembrane protein localized to the limiting membrane of the lysosome. There is no cure for NP-C but there is a disease-modifying drug (miglustat) that slows disease progression but with associated side effects. Here, we demonstrate in a well-characterized mouse model of NP-C that a single administration of AAV-mediated gene therapy to the brain can significantly extend lifespan, improve quality of life, prevent or ameliorate neurodegeneration, reduce biochemical pathology and normalize or improve various indices of motor function. Over-expression of human NPC1 does not cause adverse effects in the brain and correctly localizes to late endosomal/lysosomal compartments. Furthermore, we directly compare gene therapy to licensed miglustat. Even at a low dose, gene therapy has all the benefits of miglustat but without adverse effects. On the basis of these findings and on-going ascendency of the field, we propose intracerebroventricular gene therapy as a potential therapeutic option for clinical use in NP-C.

Oxidative addition of TMEDA-supported [AlH2]+ to [{BDI}Ga] (BDI = {HC(C(CH3)N(2,6-iPr2-C6H3))2) provides [{BDI}Ga(H)-Al(H)(tmeda)]¬[B(C6H3-3,5-Me2)4] (TMEDA = N,N,N’N’-tetramethylethylene¬diamine) with a covalent metal-metal bond. The reaction is readily reversed by substituting TMEDA for an...

HLA may influence the natural history of some diseases. HLA frequencies have been compared in 164 healthy control subjects, 50 patients with sarcoid lung fibrosis, and 37 patients with sarcoidosis that resolved spontaneously. B8 was increased significantly in the resolved group compared to both healthy control subjects (p <0001) and the fibrotic group (p <0 01). The results support the findings of other investigators, and are consistent with the hypothesis that inherited host factors, perhaps related to immune response, influence the clinical expression of sarcoidosis.

Acetyl-DL-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies acetyl-DL-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-DL-leucine and its enantiomers acetyl-L-leucine and acetyl-D-leucine in symptomatic Npc1-/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-DL-leucine. When acetyl-DL-leucine and acetyl-L-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-D-leucine did not. These data are consistent with acetyl-L-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the L enantiomer in Npc1-/- mice. When the standard of care drug miglustat and acetyl-DL-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-DL-leucine treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of acetyl-DL-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.