Objective: To inform selection of doses of SBT101 for a first-in-human clinical study. SBT101 is an adeno-associated virus serotype 9 (AAV9)-based gene therapy candidate intended to deliver a functional copy of the human ABCD1 gene in development as a treatment for adrenomyeloneuropathy (AMN).
Background: AMN is an inherited neurodegenerative disease caused by pathogenic variants in the ABCD1 gene which encodes a peroxisomal transporter for very long-chain fatty acids (VLCFA). AMN typically occurs in adulthood and is characterized by a slowly progressive spinal cord disease leading to loss of mobility, incontinence, and debilitating pain. Currently, there is no treatment for AMN.
Method: Safety, efficacy, and biodistribution data from preclinical studies in rodents and non-human primates (NHPs) were used to select appropriate clinical doses of SBT101 for a planned Phase 1/2 study.
Results: In an 8‑week dose-finding study, intrathecal (IT) administration of SBT101 led to dose‑dependent increases in human ABCD1 protein levels in the spinal cords of Abcd1-/y mice, and at a dose of 2.0E10 vector genomes/animal (vg/an) mitochondrial DNA levels were significantly improved versus untreated controls. In Abcd1-/y/Abcd2-/- mice, increased grip strength (equivalent to wild-type) and dose-dependent reductions in VLCFA were observed 7–8 months after receiving SBT101 at 3.3E10 and 3.3E11 vg/an compared with control mice (AAV9-Null). A dose of 2.0E10 vg/an was considered the minimum effective dose in mice, translating to 7.5E13 vg/person in humans, based on relative volumes of cerebrospinal fluid. In biodistribution studies in NHPs, IT administration of rAAV9-CBA-GFP-WPRE (encoding a reporter gene) at 1.1E13 and 3.4E13 vg/an led to expression of the reporter gene in 25–100% of spinal cord and dorsal root ganglia (DRG) neurons. One-time IT administration of SBT101 at doses ≤ 7.6E13 vg/an in NHPs (equivalent to human doses ≤ 8.8E14 vg/person) was well tolerated.
Conclusion: Based on these findings, a first-in-human dose range of SBT101 was calculated to be 1.0E14–3.0E14 vg/person. Equivalent doses demonstrated activity and efficacy in mice, efficient transduction of spinal cord and DRG neurons in NHPs at > 25%, and were well tolerated with a high-dose safety margin of approximately 2.75‑fold.
To cite this abstract in AMA style:
D. Anderson, C. Maguire, C. Ng, Y. Gong, F. Eichler, S. Fourcase, C. Guilera, A. Pujol, A. Onieva, M. Leal-Julià, S. Verdés, A. Bosch, I. Dijkstra, S. Kemp, H. Park, T. Del Rio, T. Lutz, V. Vasireddy, S. Clark, K. Kozarsky. Selection of clinical doses for SBT101, an AAV9-hABCD1 vector for the treatment of adrenomyeloneuropathy [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/selection-of-clinical-doses-for-sbt101-an-aav9-habcd1-vector-for-the-treatment-of-adrenomyeloneuropathy/. Accessed June 14, 2025.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/selection-of-clinical-doses-for-sbt101-an-aav9-habcd1-vector-for-the-treatment-of-adrenomyeloneuropathy/