PMID- 30073179
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 10
DP  - 2018 Sep 21
TI  - Toxicology Study of Intra-Cisterna Magna Adeno-Associated Virus 9 Expressing 
      Human Alpha-L-Iduronidase in Rhesus Macaques.
PG  - 79-88
LID - 10.1016/j.omtm.2018.06.003 [doi]
AB  - Mucopolysaccharidosis type I is a recessive genetic disease caused by deficiency 
      of the lysosomal enzyme alpha-L-iduronidase, which leads to a neurodegenerative and 
      systemic disease called Hurler syndrome in its most severe form. Several clinical 
      trials are evaluating adeno-associated virus serotype 9 (AAV9) for the treatment 
      of neurodegenerative diseases. Although these trials focus on systemic or lumbar 
      administration, intrathecal administration via suboccipital puncture into the 
      cisterna magna has demonstrated remarkable efficacy in large animals. We, 
      therefore, conducted a good laboratory practice-compliant non-clinical study to 
      investigate the safety of suboccipital AAV9 gene transfer of human 
      alpha-L-iduronidase into nonhuman primates. We dosed 22 rhesus macaques, including 
      three immunosuppressed animals, with vehicle or one of two doses of vector. We 
      assessed in-life safety and immune responses. Animals were euthanized 14, 90, or 
      180 days post-vector administration and evaluated for histopathology and 
      biodistribution. No procedure-related lesions or adverse events occurred. All 
      vector-treated animals showed a dose-dependent mononuclear pleocytosis in the 
      cerebrospinal fluid and minimal to moderate asymptomatic degeneration of dorsal 
      root ganglia neurons and associated axons. These studies support the clinical 
      development of suboccipital AAV delivery for Hurler syndrome and highlight a 
      potential sensory neuron toxicity that warrants careful monitoring in 
      first-in-human studies.
FAU - Hordeaux, Juliette
AU  - Hordeaux J
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Hinderer, Christian
AU  - Hinderer C
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Goode, Tamara
AU  - Goode T
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Katz, Nathan
AU  - Katz N
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Buza, Elizabeth L
AU  - Buza EL
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Bell, Peter
AU  - Bell P
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Calcedo, Roberto
AU  - Calcedo R
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Richman, Laura K
AU  - Richman LK
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
FAU - Wilson, James M
AU  - Wilson JM
AD  - Gene Therapy Program, Department of Medicine, University of Pennsylvania, 
      Perelman School of Medicine, Philadelphia, PA 19104, USA.
LA  - eng
PT  - Journal Article
DEP - 20180714
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC6070681
OTO - NOTNLM
OT  - AAV9
OT  - MPS I
OT  - intrathecal
EDAT- 2018/08/04 06:00
MHDA- 2018/08/04 06:01
PMCR- 2018/07/14
CRDT- 2018/08/04 06:00
PHST- 2018/04/06 00:00 [received]
PHST- 2018/06/07 00:00 [accepted]
PHST- 2018/08/04 06:00 [entrez]
PHST- 2018/08/04 06:00 [pubmed]
PHST- 2018/08/04 06:01 [medline]
PHST- 2018/07/14 00:00 [pmc-release]
AID - S2329-0501(18)30057-3 [pii]
AID - 10.1016/j.omtm.2018.06.003 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2018 Jul 14;10:79-88. doi: 10.1016/j.omtm.2018.06.003. 
      eCollection 2018 Sep 21.