An in vitro and in vivo efficacy evaluation of gene therapy candidate SBT101 in mouse models of adrenomyeloneuropathy and in NHPs

Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the <i>ABCD1</i> gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human <i>ABCD1</i> [h<i>ABCD1</i>]), aims to ameliorate pathology by delivering functional copies of h<i>ABCD1</i> to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect. <i>In vitro</i> and <i>in vivo</i> mouse studies were conducted to assess the biochemical and functional efficacy of SBT101 and show effective delivery to target tissues involved in the disease pathology: spinal cord and dorsal root ganglia. Administration of SBT101 to mixed glial cell cultures from <i>Abcd1</i>-Null mice, and to male <i>Abcd1</i> knockout (<i>Abcd1</i> ^<i>-/y</i> ) and double-knockout (<i>Abcd1</i> ^<i>-/y</i> /<i>Abcd2</i> ^<i>-/-</i> ) mice led to increased hABCD1 production and reduced VLCFA. Double-knockout mice also exhibited improved grip strength. Furthermore, we conducted biodistribution and safety assessments in nonhuman primates. Six-hour intrathecal lumbar infusions demonstrated effective transduction throughout target tissues, supporting the clinical feasibility of the procedure. SBT101 was well tolerated, with no observed SBT101-related mortality or clinical signs. These findings not only provide preclinical efficacy data for SBT101 but also inform clinically relevant SBT101 dose selection for patients with adrenomyeloneuropathy.