CommentaryTherapy for Gaucher disease: Don’t stop thinking about tomorrow
Section snippets
Substrate reduction therapy
One different approach to treating Gaucher disease is the use of inhibitors of glycosphingolipid (GSL) synthesis. Several drugs with this capability are available, including inhibitors that resemble the substrates or products of GSL synthases, and have been shown to decrease glucocerebroside (glucosylceramide) levels in vitro and in vivo [11]. In Gaucher disease, small molecule iminosugar-derivative inhibitors, such as N-butyldeoxynorjirimycin, have been used to reduce the synthesis of
Stem cell and viral-mediated gene therapy for Gaucher disease
Because Gaucher disease can be cured by replacing the patient’s defective hematopoietic stem cells with genetically normal stem cells, as in bone marrow transplantation, correction of the defect in the patient’s own hematopoietic stem cells should be an effective way to treat this disease. However, because stem cells that produce glucocerebrosidase may not have a proliferative advantage over those that do not, a cure would be realized only if the patient’s untransduced cells were at least
Chaperone therapy
More recently, pharmacologic chaperones have been proposed as a potential therapy for patients with Gaucher disease [23]. Chaperone therapy is directed at correcting protein misfolding or mistrafficking by stabilizing the mutant protein with small chemical inhibitors that can reversibly bind to the enzyme [24], [25]. The small molecules “rescue” the misfolded protein, preventing its degradation and enabling it to arrive and function at its lysosomal destination. Large scale screening of
Strategies to improve enzyme replacement therapy
While the above modalities, alone or in concert, may have potential for the treatment of some patients, ERT is still the only form of therapy with a proven track record for Gaucher disease. Thus, we suggest that a greater focus on improving enzyme delivery and reducing production costs is warranted. Such strategies include receptor-dependent and -independent enzyme fusion proteins, immunotargeting of glucocerebrosidase and increasing enzyme production.
Imiglucerase (Cerezyme®, Genzyme Corp.) is
Conclusion
Today, imiglucerase therapy for Gaucher disease, with its ten-year record of efficacy and safety, has become a prototype for developing treatments for other metabolic storage disorders. However, this success should not be a reason for complacency. While this relatively efficacious, albeit costly, therapy is providing much needed stabilization for the patient population, it is time to bring complementary or improved treatments into the clinic. ERT, as currently administered, may not be
Acknowledgment
This work was supported by the Intramural Research Programs of the NIH and NHGRI. E.I.G. is a founder of Targeted Cell Therapies, a company developing macrophage mediated gene therapy for Gaucher disease.
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Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases
2011, Journal of Biological ChemistryCitation Excerpt :Although its safety and effectiveness has been demonstrated for several other LSD, including Fabry and Pompe disease, enzyme replacement therapy fails to provide economically sustainable treatment and efficiently address several aspects of the disease. Specifically, enzyme replacement therapy is limited to the treatment of non-neuronopathic symptoms due to inability of the intravenously injected recombinant enzyme to cross the blood-brain barrier (34, 35). A number of highly prevalent alleles associated with LSD development contain non-inactivating, destabilizing mutations.
Hematopoietic stem cell expansion and gene therapy
2011, CytotherapyCitation Excerpt :Similarly, in an ADA-SCID gene therapy trial, discontinuation of enzyme replacement therapy following transplantation of gene-modified HSC promoted their selective survival over mutant counterparts (18). In contrast, in the setting of gene therapy for Fanconi anemia and Gaucher Disease, where no preparative regimen was used and no selective advantage for gene-modified cells was either present or implemented in vivo, the therapeutic efficacy of HSC gene therapy fell short, compounded by early, inefficient transduction protocols (19,20). One of the foremost limitations of current gene therapy protocols is the difficulty in striking a tenuous balance between in vivo selection of cells and pre-transplant conditioning.
Lacidipine remodels protein folding and Ca<sup>2+</sup> homeostasis in Gaucher's disease fibroblasts: A mechanism to rescue mutant glucocerebrosidase
2011, Chemistry and BiologyCitation Excerpt :As a result, these unstable GC variants retain biologic activity if forced to fold into their native 3D structure (Sawkar et al., 2002, 2006; Yu et al., 2007). Rescuing the function of mutated GC variants is an appealing alternative to the currently available therapeutic options (mainly enzyme replacement therapy [Cerezyme®]), which are inadequate for the treatment of neuronopathic forms of GD (Sidransky et al., 2007). Hence, considerable effort has been recently devoted to the design of strategies to rescue cellular folding, trafficking, and activity of mutated GC variants associated with neuronopathic GD (Mu et al., 2008a, 2008b; Ong et al., 2010; Wang et al., 2011), the most common being the severely destabilized L444P GC variant, which is associated with complete loss of activity and neuronopathic symptoms in homozygous patients (Grabowski, 1997).
Bone involvement during revealed late Gaucher's disease
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