An in vitro and in vivo efficacy evaluation of gene therapy candidate SBT101 in mouse models of adrenomyeloneuropathy and in NHPs
Vasireddy, Vidyullatha (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)
Maguire, Casey A. (Harvard Medical School)
Anderson, David W. (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)
Ng, Carrie (Harvard Medical School)
Gong, Yi (Harvard Medical School)
Eichler, Florian (Harvard Medical School)
Fourcade, Stéphane (Institut d'Investigació Biomèdica de Bellvitge)
Guilera, Cristina (Institut d'Investigació Biomèdica de Bellvitge)
Onieva Salgado, Andrea (Universitat Autònoma de Barcelona. Institut de Neurociències)
Sanchez, Angela (Universitat Autònoma de Barcelona. Institut de Neurociències)
Leal-Julià, Marc (Universitat Autònoma de Barcelona. Institut de Neurociències)
Verdés, Sergi (Universitat Autònoma de Barcelona. Institut de Neurociències)
Dijkstra, Inge M.E. (Amsterdam UMC. University Medical Center)
Kemp, Stephan (Amsterdam UMC. University Medical Center)
Park, HongGeun (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)
Lutz, Tiffany (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)
Clark, Sean W. (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)
Bosch i Merino, Assumpció (Universitat Autònoma de Barcelona. Institut de Neurociències)
Pujol, Aurora 1968- (Institut d'Investigació Biomèdica de Bellvitge)
Kozarsky, Karen (SwanBio Therapeutics, Inc., Philadelphia, PA, USA)

Data:	2024
Resum:	Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the ABCD1 gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human ABCD1 [h ABCD1 ]), aims to ameliorate pathology by delivering functional copies of h ABCD1 to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect. In vitro and in vivo 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 Abcd1 -Null mice, and to male Abcd1 knockout (Abcd1 -/y ) and double-knockout (Abcd1 -/y / Abcd2 -/- ) 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. Kozarsky and colleagues report effective biodistribution of an AAV9 vector throughout the central nervous system, and safety of SBT101 (gene therapy candidate for adrenomyeloneuropathy), following intrathecal administration in mouse models of disease and in nonhuman primates. Observed biodistribution highlights the potential of using intrathecally administered AAV9-based therapies in other diseases.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Adeno-associated virus ; Adrenomyeloneuropathy ; Biodistribution ; Gene therapy ; Human ABCD1 ; In vivo mouse model ; Neurodegenerative disease ; Nonhuman primates ; SBT101 ; Very-long-chain fatty acids
Publicat a:	Molecular Therapy. Methods & Clinical Development, Vol. 32 (december 2024) , ISSN 2329-0501

DOI: 10.1016/j.omtm.2024.101354
PMID: 39524975

16 p, 3.9 MB

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