Fabry disease, treatment

In the cases of Gaucher disease and Fabry disease, it is hoped that treatment of infants and young children may prevent brain damage. However, in Tay-Sachs disease the primary sites of accumulation of the ganglioside GM2 are the ganglion and glial cells of the brain. Because of the "blood-brain barrier" and the severity of the damage it seems less likely that the disease can be treated successfully. 

Breunig, F., Weidemann, F., Beer, M., Eggert, A., Krane, V., Spindler, M., Sandstede, J., Strotmann, J. and Wanner, C. (2003). Fabry disease Diagnosis and treatment. Kidney Int. 84(Suppl.), S181-S185. 

What is evident immediately on attempting to develop a therapy for any particular LSD is the scant (and for many LSDs, virtually absent) information on disease pathophysiology. Beyond recognition of the enzyme deficiency responsible for the disease and the biochemistry of the accumulating substrate, much of the literature is in the form of case reports on individuals or small patient sets, often with minimal characterization of disease pathology. The paradox is that a more complete body of literature only develops after an effective treatment becomes available (e.g., Gaucher and Fabry diseases). Considerable initial research is therefore needed by any company seeking a successful therapeutic for a specific LSD. 

Severe neurological involvement in SLE particularly during acute onset is a particularly devastating diagnosis. Management of CNS SLE is reviewed by Sanna et al., 2003a. Cyclophosphamide is the treatment of choice for severe acute non-thrombotic CNS disease. Treatment with steroids versus immunosuppressant therapy with cyclophosphamide is evaluated in a controlled clinical trial of 32 SLE patients with onset of severe neuropsychiatric involvement for < 15 days. Induction treatment involved IV methylprednisolone (3 g) followed by either IV monthly cyclophosphamide or IV MP every 3 m for 1 year. Overall response rate was 75% for either treatment but those on cyclophosphamide had a significandy better response to treatment (p < 0.03) (Barile-Fabris et al., 2005). 

IR imaging has also been used to investigate mouse models of human disease, including Fabry disease (a Upid storage disease) [50] and skeletal disorders. Gamacho et al. characterized bone mineraUzation in a mouse model of osteogenesis imperfecta (OI) after treatment with the bisphosphonate alendronate (ALN) [51]. The treatment of OI mouse models with ALN led to improved mechanical... 

There are over 40 lysosomal storage disorders (LSDs) characterized by the specific enzyme deficiency and accumulated substrate. Pathologies associated with LSDs are multisystemic and variable including CNS, skeletal, cardiovascular, renal, and ocular system involvement. The aggregate incidence is estimated to approach 1 in 7000 live births (Ellinwood et al., 2004). Inheritance for LSDs is primarily autosomal recessive with the exception of two X-linked diseases (Fabry and mucopolysaccharidosis (MPS) II). Treatment for LSDs relies on providing functional enzyme to the lysosomes of affected cells and has traditionally been confined to bone marrow transplantation, and enzyme replacement therapy (ERT). 

Treatment of sphingolipidoses is primarily symptomatic and supportive. For example, in patients with anemia due to Gaucher s disease, thrombocytopenia associated with hypersplenism is relieved by splenectomy. Infusion of appropriate purified human placental tissue enzymes in patients with Gaucher s disease and Fabry s disease reduced the accumulated glycolipids in the circulation and liver. Recent advances in the cloning and amplification of human DNA segments in bacterial plasmids... 

It will be of interest in the future to contrast the success of enzyme replacement that requires infusion with orally delivered drugs for the treatment of Gaucher s and Fabry s diseases. Oral drugs are clearly more convenient however, the side effects and long-term toxicity must be determined. 

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