Therapies

While symptom management may improve a patient’s quality of life, treatment to prevent or reverse accumulation of GL-3 and offers the potential to stem disease progression and prevent organ damage.

There are other treatments for Fabry disease that are currently under investigation. They include:

• Endogenous replacement of the alpha-GAL gene
• Substrate inhibition therapy to reduce glycosphingolipid synthesis within the cell

^{Enzyme Replacement Therapy (ERT)}

ERT has been approved for use in many countries throughout the world including the United States and those in the European Union.

^{Gene therapy}

Gene therapy for Fabry disease is in the early stages of investigation. Research has identified two different approaches:

• Direct delivery of the alpha-GAL gene using modified adenoviral and adeno-associated viral vectors in order to genetically modify the liver, lung, or muscle of the patient and use these organs as internal sources of alpha-GAL^[1,2]
• Genetic alteration of hematopoietic stem cells from Fabry patients to produce alpha-GAL and restoration of the altered cells to the patient through bone marrow transplantation^[3,4]

Both methods have shown potential promise in pre-clinical studies in Fabry mice.^[2,5]

^{Small molecule approaches}

Research has also identified two approaches involving “small molecules.” Both of these require some residual alpha-GAL activity to be effective and could potentially be used in conjunction with either gene therapy or enzyme replacement therapy.

The first approach involves substrate inhibition therapy to reduce cellular synthesis of glycosphingolipids.^[6] Two potentially promising small molecules are N-butyldeoxynojirimycin and D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4).^[6,7]

A second approach involves use of a competitive inhibitor of alpha-GAL to increase the activity of residual enzyme. In animal studies, oral administration of small doses of 1-deoxy-galactonojirinmycin increased the transport and maturation of mutant alpha-GAL, and increased alpha-GAL activity in some organs.^[8]

^References

1. Ohsugi K, Kobayashi K, Itoh K, Sakuraba H, Sakuragawa N. Enzymatic corrections for cells derived from Fabry disease patients by a recombinant adenovirus vector. J Hum Genet. 2000;45:1-5.

2. Ziegler RJ, Yew NS, Li C, et al. Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer. Hum Gene Ther. 1999;10:1667-1682.

3. Takiyama N, Dunigan JT, Vallor MJ, Kase R, Sakuraba H, Barranger JA. Retrovirus-mediated transfer of human alpha-galactosidase A gene to human CD34+ hematopoietic progenitor cells. Hum Gene Ther. 1999;10:2881-2889.

4. Takenaka T, Hendrickson CS, Tworek DM, et al. Enzymatic and functional correction along with long-term enzyme secretion from transduced bone marrow hematopoietic stem/progenitor and stromal cells derived from patients with Fabry disease. Exp Hematol. 1999;27:1149-1159.

5. Takenaka T, Murray GJ, Qin G, et al. Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. Proc Natl Acad Sci U S A. 2000;97:7515-7520.

6. Platt FM, Butters TD. New therapeutic prospects for the glycosphingolipid lysosomal storage diseases. Biochem Pharmacol. 1998;56:421-430.

7. Abe A, Gregory S, Lee L, et al. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest. 2000;105:1563-1571.

8. Fan J-Q, Ishi S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med. 1999;5:112-115.