title: Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model.
abstract: GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment.
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gray-Edwards
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Debra S
authors.initials: DS
authors.lastname: Regier
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Shirley
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Randle
authors.affiliation: MR R&D, Siemens Healthcare, Malvern, PA 19355, USA.
authors.forename: Nouha
authors.initials: N
authors.lastname: Salibi
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Thomas
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Latour
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Johnston
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Annie S
authors.initials: AS
authors.lastname: Maguire
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Taylor
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sorjonen
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: McCurdy
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Christopherson
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Bradbury
authors.affiliation: Department of Electrical and Computer Engineering, Auburn University, Auburn, AL 36849, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Beyers
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Aime K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Brunson
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cox
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Baker
authors.affiliation: Department of Electrical and Computer Engineering, Auburn University, Auburn, AL 36849, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Denney
authors.affiliation: Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA. Electronic address: martidr@auburn.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D002415:Cats; D000229:Dependovirus / Q000145:classification / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography; D016537:Gangliosidosis, GM1 / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D006996:Hypocalcemia / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers
keywords: AAV gene therapy; gangliosidosis; lysosomal storage disorders; neurodegeneration