This study explored the feasibility of intraparenchymal delivery (gadoteridol and/or Serotype 5 Adeno-Associated Viral Vector-enhanced Green Fluorescent Protein [AAV5-eGFP]) into the cerebellum of nonhuman primates using real-time magnetic resonance imaging-guided convection enhanced delivery (MRI-CED) technology. All animals tolerated the neurosurgical procedure without any clinical sequela. Gene expression was detected within the cerebellar parenchyma at the site of infusion and resulted in transduction of neuronal cell bodies and fibers. Histopathology indicated localized damage along the stem of the cannula tract. These findings demonstrate the potential of real-time MRI-CED to deliver therapeutics into the cerebellum, which has extensive reciprocal connections and may be used as a target for the treatment of neurological disorders.
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References
1.
ReeberSL, OtisTS, SillitoeRV. New roles for the cerebellum in health and disease. Front Syst Neurosci, 2013; 7:83.
2.
SokolovAA, MiallRC, IvryRB. The cerebellum: Adaptive prediction for movement and cognition. Trends Cogn Sci, 2017; 21:313–332.
3.
GellersenHM, GuoCC, O'CallaghanC, et al.Cerebellar atrophy in neurodegeneration—a meta-analysis. J Neurol Neurosurg Psychiatry, 2017; 88:780–788.
4.
O'CallaghanC, HornbergerM, BalstersJH, et al.Cerebellar atrophy in Parkinson's disease and its implication for network connectivity. Brain, 2016; 139:845–855.
WuT, HallettM. The cerebellum in Parkinson's disease. Brain, 2013; 136:696–709.
7.
DeuschlG, WenzelburgerR, LofflerK, et al.Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain, 2000; 123:1568–1580.
8.
NeychevVK, FanX, MitevVI, et al.The basal ganglia and cerebellum interact in the expression of dystonic movement. Brain, 2008; 131:2499–2509.
9.
ShakkottaiVG.Physiologic changes associated with cerebellar dystonia. Cerebellum, 2014; 13:637–644.
10.
FasanoA, LaganiereSE, LamS, et al.Lesions causing freezing of gait localize to a cerebellar functional network. Ann Neurol, 2017; 81:129–141.
11.
SeidelK, BouzrouM, HeidemannN, et al.Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies. Ann Neurol, 2017; 81:898–903.
12.
GuoCC, TanR, HodgesJR, et al.Network-selective vulnerability of the human cerebellum to Alzheimer's disease and frontotemporal dementia. Brain, 2016; 139:1527–1538.
13.
ReesEM, FarmerR, ColeJH, et al.Cerebellar abnormalities in Huntington's disease: a role in motor and psychiatric impairment?. Mov Disord, 2014; 29:1648–1654.
14.
TanRH, DevenneyE, Dobson-StoneC, et al.Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One, 2014; 9:e105632.
15.
VincentGK, Velkoff VAU.S. Census Bureau. The next four decades: The older population in the United States: 2010 to 2050. Washington, DC: U.S. Dept. of Commerce, Economics and Statistics Administration, U.S. Census Bureau, 2010
KellsAP, HadaczekP, YinD, et al.Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc Natl Acad Sci U S A, 2009; 106:2407–2411.
18.
SalegioEA, StreeterH, DubeN, et al.Distribution of nanoparticles throughout the cerebral cortex of rodents and non-human primates: Implications for gene and drug therapy. Front Neuroanat, 2014; 8:9.
19.
SuX, KellsAP, SalegioEA, et al.Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther, 2010; 18:1490–1495.
20.
San SebastianW, RichardsonRM, KellsAP, et al.Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum. Hum Gene Ther, 2012; 23:210–217.
21.
SanftnerLM, SommerJM, SuzukiBM, et al.AAV2-mediated gene delivery to monkey putamen: Evaluation of an infusion device and delivery parameters. Exp Neurol, 2005; 194:476–483.
22.
ChittiboinaP, HeissJD, WarrenKE, et al.Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas. J Neurosurg Pediatr, 2014; 13:276–282.
23.
San SebastianW, KellsAP, BringasJ, et al.Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate. Mol Ther Methods Clin Dev, 2014; 3:14049.
24.
BuJ, AsheKM, BringasJ, et al.Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A. Mol Ther, 2012; 20:1893–1901.
25.
SalegioEA, SamaranchL, KellsAP, et al.Guided delivery of adeno-associated viral vectors into the primate brain. Adv Drug Deliv Rev, 2012; 64:598–604.
26.
AliskyJM, HughesSM, SauterSL, et al.Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors. Neuroreport, 2000; 11:2669–2673.
27.
DavidsonBL, SteinCS, HethJA, et al.Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci U S A, 2000; 97:3428–3432.
28.
KaemmererWF, ReddyRG, WarlickCA, et al.In vivo transduction of cerebellar Purkinje cells using adeno-associated virus vectors. Mol Ther, 2000; 2:446–457.
29.
SamaranchL, BlitsB, San SebastianW, et al.MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther, 2017; 24:253–261.
30.
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. The Guide for the Care and Use of Laboratory Animals, 8th ed. Washington, DC: National Academies Press, 2011.
31.
SchombergD, WangA, MarshallH, et al.Ramped-rate vs continuous-rate infusions: An in vitro comparison of convection enhanced delivery protocols. Ann Neurosci, 2013; 20:59–64.
32.
SzerlipNJ, WalbridgeS, YangL, et al.Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg, 2007; 107:560–567.
33.
LonserRR, WalbridgeS, GarmestaniK, et al.Successful and safe perfusion of the primate brainstem: In vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg, 2002; 97:905–913.
34.
RichardsonRM, KellsAP, MartinAJ, et al.Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg, 2011; 89:141–151.
35.
SalegioEA, SamaranchL, KellsAP, et al.Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Ther, 2013; 20:348–352.
36.
JeuneVL, JoergensenJA, HajjarRJ, et al.Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods, 2013; 24:59–67.
37.
FaleseL, SandzaK, YatesB, et al.Strategy to detect pre-existing immunity to AAV gene therapy. Gene Ther, 2017; 24:768–778.
38.
KellyRM, StrickPL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci, 2003; 23:8432–8444.
39.
YuH, SternadD, CorcosDM, et al.Role of hyperactive cerebellum and motor cortex in Parkinson's disease. Neuroimage, 2007; 35:222–233.
40.
BostanAC, DumRP, StrickPL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A, 2010; 107:8452–8456.
41.
HoshiE, TremblayL, FegerJ, et al.The cerebellum communicates with the basal ganglia. Nat Neurosci, 2005; 8:1491–1493.
