Abstract Details

Adrenomyeloneuropathy is a form of X-linked Adrenoleukodystrophy caused by mutations in the gene encoding the ATP Binding Cassette subfamily D member-1 (hABCD1), characterized by a dying-back axonopathy affecting SC tracts and ultimately leading to loss of mobility. We are developing SBT101, an AAV9-based gene therapy encoding a functional hABCD1, for use as a treatment for AMN. Prior research suggests 24-hour IT administration delivered biodistribution to the entire SC/DRG as compared with other methods of delivery. We have assessed multiple infusion parameters to enhance widespread SC/DRG distribution following intrathecal delivery of a vector.

Evaluate intrathecal administration (IT) delivery parameters of an AAV9 to produce widespread gene transfer/biodistribution within the spinal cord (SC) and dorsal root ganglia (DRG), for a gene therapy to AMN.

Preclinical studies were carried out to assess delivery of an AAV9-GFP reporter vector to further understand intrathecal delivery infusion parameters and the effect on biodistribution throughout the SC/DRG in NHPs. Animals received either a bolus (20 min) or extended (6 or 24-hour) infusion of AAV9-GFP at one of two sites (cervical or lumbar) utilizing doses of 3.25E13 vector genomes (vg) or 9.75E13 vg per animal, with a total delivered volume between 2.5-10 mL followed by a 14-day survival and immunohistochemical (IHC) analysis of GFP throughout multiple tissues.

24-hour lumbar infusion delivered widespread biodistribution to the entire SC and DRG compared to either cervical or bolus delivery.  Further it was found that a 6-hour lumbar infusion was equivalent to the 24-hour infusion for biodistribution to the SC/DRG, while total volume delivered did not significantly enhance biodistribution. 

These results provide evidence that a 6-hour intrathecal lumbar infusion of an AAV9 vector can deliver widespread biodistribution to the SC/DRG comparable to or potentially above a 24-hour or bolus infusion respectively, at doses predicted to be clinically relevant in patients