Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients

ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia

“…At the same time, severely afflicted patients need to be treated early in life to avoid irreversible pathologic consequences. 31 In the current study, we demonstrate the benefit of combining ImmTOR with AAV gene therapy in a mouse model of IMMA. While a therapeutic dose of Anc80-MMUT showed long-term efficacy in the MCK-MMUT model, similar to that previously reported, the inclusion of ImmTOR provided additional therapeutic benefit both at the first dose and with repeat dosing.…”

“…Specifically, it is certain that repeat systemic gene therapy in pediatric patients using AAV vectors will not be effective (and may potentially even be detrimental) due to de novo formation of vector-induced Nabs against capsid proteins, possibly accompanied by induction of other adaptive immune responses to vector and transgene. 31,40 Therefore, the ability to mitigate the immune response to AAV vectors in a targeted fashion is a highly desirable tool for a future gene therapeutic armamentarium and may potentially cover a broad range of applications.…”

“…formation. Various strategies have been described to enable re-dosing or dosing of intravenously administered AAV in the presence of preexisting antibodies, such as combination immunosuppressive drug therapy, 31,[50][51][52] decoy empty capsids 53 , plasmapheresis, [54][55][56][57][58] and most recently an IgG-specific protease. 59 Some immunosuppressive regimens are inadequate to enable re-dosing, and some specific immunosuppressive drugs may be counterproductive by suppressing Tregs as well as effector T cells.…”

“…Similarly, daily administration of free rapamycin for more than 3 weeks was only partially efficient in prevention of immune response to AAV vector in a rat model of Crigler-Najjar syndrome and was completely ineffective in animals with prior AAV exposure. 31…”

“…28,29 Moreover, co-administration of liver-tropic AAV vectors and ImmTOR leads to immediate increase of transgene expression even after the first dose, most likely due to elevated uptake by liver cells and rapamycin-induced autophagy. [29][30][31] In this study, we evaluated the safety and therapeutic efficacy of an ImmTOR and AAV vector combination in a mouse model of IMMA using a vector pseudoserotyped with Anc80, a rationally engineered AAV capsid. 32 Repeated co-administration of Anc80-MMUT and ImmTOR was well tolerated and led to nearly complete inhibition of the formation of immunoglobulin G (IgG) antibodies to Anc80.…”