Prospects of TAT-mediated protein therapy for fragile X syndrome.

Fragile X syndrome is due to the absence of the fragile X mental retardation protein (FMRP). Patients are mentally retarded and show physical as well as behavioural abnormalities. Loss of protein in the neurons results in changes of dendrite architecture, and impairment of the pruning process has been indicated. Apart from some minor differences, no severe morphological changes have been observed in the brain. Until now, no therapy is available for fragile X patients. Recently it has been reported, that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to the protein in question. Upon production of a TAT-FMRP fusion protein in a baculovirus-expression system, we used immunohistochemistry to verify TAT-mediated uptake of FMRP in fibroblasts. However, uptake efficiency and velocity was lower than expected. Neuronal uptake was highly inefficient and the fusion protein demonstrated toxicity.