LB-11-
Results: To date, seven subjects have received a single dose of TT-034 at either 4.00E10, 1.25E11, or 4.00E11 vg/kg. Additional subjects will be enrolled in dose cohorts of 1.25E12 or 4.00E12 vg/kg. There have been no treatment-related SAEs in the study to date. Once administered, TT-034 clears from serum within the first week post dosing. No long term TT-034 shedding has been detected in the urine, stool, semen, or sputum. TT-034 DNA levels in liver biopsies are measured by QCR and are similar to those reported in NHP models. Patients administered the lowest dose resulted in 0.01 or 0.02 copies of the TT-034 genome per cell, the equivalent of 1 or 2 % hepatocyte transduction. At a dose of 1.25E11 vg/kg, substantially higher levels were detected in the hepatic tissues from the three subjects, yielding 0.48, 3.65 and 10.44 copies of TT-034 DNA per cell respectively. The first subject dosed with 4.00E11 vg/kg demonstrated 17.74 copies per cell, indi- cating that a significant portion of the hepatocytes may have been transduced. QPCR analyses of RNA isolated from the biopsies confirmed concomitant, dose dependent expression of anti-HCV shRNAs. Copy numbers of shRNA6, shRNA19 and shRNA22 were measured at 66, 2032, and 99 copies per cell respectively in the subject dosed with 4.00E11 vg/ kg. Conclusion: Initial doses of TT-034 are well tolerated in human subjects infected with HCV. At higher doses, substantial portions of hepatocytes are transduced and result in concurrent dose-dependent expression of anti-HCV shRNAs.
http://www.aasld.org/sites/default/files/TLM-2015-LakeBreakin
