科研之友
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摘要
Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the -subunit of Hex (TSD ) or a mixture of two vectors encoding both the and subunits separately (TSD + ) injected at high (1.3x10(13) vector genomes) or low (4.2x10(12) vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD + sheep compared to TSD sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD + ), and ganglioside clearance was most widespread in the TSD + high-dose sheep. Microglial activation and proliferation in TSD sheepmost prominent in the cerebrumwere attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.
- 出版日期2018-3
