Commentary
Therapy for Gaucher disease: Don’t stop thinking about tomorrow

https://doi.org/10.1016/j.ymgme.2006.09.007Get rights and content

Abstract

While enzyme replacement therapy for Gaucher disease has been widely used and appears to be an efficacious and safe treatment, this success should not be a reason for complacency. Other treatment strategies currently under consideration for patients with Gaucher disease include gene therapy, substrate reduction therapy and chaperone therapy. Furthermore, improvements in enzyme therapy could also have a significant clinical impact. Individuals with Gaucher disease and other lysosomal disorders will greatly benefit from continual refinement and optimization of the current therapy, as well as from the development of new treatment modalities that offer improvements in efficacy, cost, safety and availability.

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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