Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy
Rachel M Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J Gray, Rachel M Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J Gray
Abstract
An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://ichgcp.net/clinical-trials-registry/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs). The pathologic signature of GAN is giant axonal swellings filled with disorganized accumulations of IFs. Herein, we describe the development and characterization of the AAV vector carrying a normal copy of the human GAN transgene (AAV9/JeT-GAN) currently employed in the clinical trial. Treatment with AAV/JeT-GAN restored the normal configuration of IFs in patient fibroblasts within days in cell culture and by 4 weeks in GAN KO mice. IT delivery of AAV9/JeT-GAN in aged GAN KO mice preserved sciatic nerve ultrastructure, reduced neuronal IF accumulations and attenuated rotarod dysfunction. This strategy conferred sustained wild-type gigaxonin expression across the PNS and CNS for at least 1 year in mice. These results support the clinical evaluation of AAV9/JeT-GAN for potential therapeutic outcomes and treatment for GAN patients.
Keywords: AAV9; adeno-associated virus; biodistribution; dorsal root ganglia; fibroblast; gene therapy; giant axonal neuropathy; gigaxonin; intrathecal; sciatic nerve.
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References
- Asbury A.K., Gale M.K., Cox S.C., Baringer J.R., Berg B.O. Giant axonal neuropathy—a unique case with segmental neurofilamentous masses. Acta Neuropathol. 1972;20:237–247.
- Berg B.O., Rosenberg S.H., Asbury A.K. Giant axonal neuropathy. Pediatrics. 1972;49:894–899.
- Yang Y., Allen E., Ding J., Wang W. Giant axonal neuropathy. Cell. Mol. Life Sci. 2007;64:601–609.
- Peiffer J., Schlote W., Bischoff A., Boltshauser E., Müller G. Generalized giant axonal neuropathy: a filament-forming disease of neuronal, endothelial, glial, and schwann cells in a patient without kinky hair. Acta Neuropathol. 1977;40:213–218.
- Houlden H., Groves M., Miedzybrodzka Z., Roper H., Willis T., Winer J., Cole G., Reilly M.M. New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy. J. Neurol. Neurosurg. Psychiatry. 2007;78:1267–1270.
- Yiu E.M., Ryan M.M. Genetic axonal neuropathies and neuronopathies of pre-natal and infantile onset. J. Peripher. Nerv. Syst. 2012;17:285–300.
- Johnson-Kerner B.L., Roth L., Greene J.P., Wichterle H., Sproule D.M. Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis. Muscle Nerve. 2014;50:467–476.
- Mahammad S., Murthy S.N., Didonna A., Grin B., Israeli E., Perrot R., Bomont P., Julien J.P., Kuczmarski E., Opal P., Goldman R.D. Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J. Clin. Invest. 2013;123:1964–1975.
- Igisu H., Ohta M., Tabira T., Hosokawa S., Goto I. Giant axonal neuropathy. A clinical entity affecting the central as well as the peripheral nervous system. Neurology. 1975;25:717–721.
- Ouvrier R.A. Giant axonal neuropathy. A review. Brain Dev. 1989;11:207–214.
- Mohri I., Taniike M., Yoshikawa H., Higashiyama M., Itami S., Okada S. A case of giant axonal neuropathy showing focal aggregation and hypophosphorylation of intermediate filaments. Brain Dev. 1998;20:594–597.
- Cleveland D.W., Yamanaka K., Bomont P. Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway. Hum. Mol. Genet. 2009;18:1384–1394.
- Pena S.D., Opas M., Turksen K., Kalnins V.I., Carpenter S. Immunocytochemical studies of intermediate filament aggregates and their relationship to microtubules in cultured skin fibroblasts from patients with giant axonal neuropathy. Eur. J. Cell Biol. 1983;31:227–234.
- Kantor B., Bailey R.M., Wimberly K., Kalburgi S.N., Gray S.J. Methods for gene transfer to the central nervous system. Adv. Genet. 2014;87:125–197.
- Hocquemiller M., Giersch L., Audrain M., Parker S., Cartier N. Adeno-associated virus-based gene therapy for CNS diseases. Hum. Gene Ther. 2016;27:478–496.
- Murlidharan G., Samulski R.J., Asokan A. Biology of adeno-associated viral vectors in the central nervous system. Front. Mol. Neurosci. 2014;7:76.
- Federici T., Taub J.S., Baum G.R., Gray S.J., Grieger J.C., Matthews K.A., Handy C.R., Passini M.A., Samulski R.J., Boulis N.M. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther. 2012;19:852–859.
- Samaranch L., Salegio E.A., San Sebastian W., Kells A.P., Foust K.D., Bringas J.R., Lamarre C., Forsayeth J., Kaspar B.K., Bankiewicz K.S. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum. Gene Ther. 2012;23:382–389.
- Gray S.J., Nagabhushan Kalburgi S., McCown T.J., Jude Samulski R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther. 2013;20:450–459.
- Passini M.A., Bu J., Richards A.M., Treleaven C.M., Sullivan J.A., O’Riordan C.R., Scaria A., Kells A.P., Samaranch L., San Sebastian W. Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy. Hum. Gene Ther. 2014;25:619–630.
- Meyer K., Ferraiuolo L., Schmelzer L., Braun L., McGovern V., Likhite S., Michels O., Govoni A., Fitzgerald J., Morales P. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. Mol. Ther. 2015;23:477–487.
- Mussche S., Devreese B., Nagabhushan Kalburgi S., Bachaboina L., Fox J.C., Shih H.J., Van Coster R., Samulski R.J., Gray S.J. Restoration of cytoskeleton homeostasis after gigaxonin gene transfer for giant axonal neuropathy. Hum. Gene Ther. 2013;24:209–219.
- Johnson-Kerner B.L., Ahmad F.S., Diaz A.G., Greene J.P., Gray S.J., Samulski R.J., Chung W.K., Van Coster R., Maertens P., Noggle S.A. Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin. Hum. Mol. Genet. 2015;24:1420–1431.
- Israeli E., Dryanovski D.I., Schumacker P.T., Chandel N.S., Singer J.D., Julien J.P., Goldman R.D., Opal P. Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy. Hum. Mol. Genet. 2016;25:2143–2157.
- Tornøe J., Kusk P., Johansen T.E., Jensen P.R. Generation of a synthetic mammalian promoter library by modification of sequences spacing transcription factor binding sites. Gene. 2002;297:21–32.
- Levitt N., Briggs D., Gil A., Proudfoot N.J. Definition of an efficient synthetic poly(A) site. Genes Dev. 1989;3:1019–1025.
- McCarty D.M., Monahan P.E., Samulski R.J. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 2001;8:1248–1254.
- McCarty D.M., Fu H., Monahan P.E., Toulson C.E., Naik P., Samulski R.J. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 2003;10:2112–2118.
- McCarty D.M. Self-complementary AAV vectors; advances and applications. Mol. Ther. 2008;16:1648–1656.
- Gray S.J., Matagne V., Bachaboina L., Yadav S., Ojeda S.R., Samulski R.J. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol. Ther. 2011;19:1058–1069.
- Pena S.D. Giant axonal neuropathy: intermediate filament aggregates in cultured skin fibroblasts. Neurology. 1981;31:1470–1473.
- Bomont P. Degradation of the intermediate filament family by gigaxonin. Methods Enzymol. 2016;569:215–231.
- Ding J., Allen E., Wang W., Valle A., Wu C., Nardine T., Cui B., Yi J., Taylor A., Jeon N.L. Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport. Hum. Mol. Genet. 2006;15:1451–1463.
- Dequen F., Bomont P., Gowing G., Cleveland D.W., Julien J.P. Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1. J. Neurochem. 2008;107:253–264.
- Ganay T., Boizot A., Burrer R., Chauvin J.P., Bomont P. Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice. Mol. Neurodegener. 2011;6:25.
- Hadaczek P., Eberling J.L., Pivirotto P., Bringas J., Forsayeth J., Bankiewicz K.S. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol. Ther. 2010;18:1458–1461.
- Samaranch L., Salegio E.A., San Sebastian W., Kells A.P., Bringas J.R., Forsayeth J., Bankiewicz K.S. Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum. Gene Ther. 2013;24:526–532.
- Sorrentino N.C., Maffia V., Strollo S., Cacace V., Romagnoli N., Manfredi A., Ventrella D., Dondi F., Barone F., Giunti M. A comprehensive map of CNS transduction by eight recombinant adeno-associated virus serotypes upon cerebrospinal fluid administration in pigs. Mol. Ther. 2016;24:276–286.
- King R.H.M. The pathology of peripheral nerve diseases. Adv. Clin. Neurosci. Rehabil. 2006;6:16–18.
- Tandan R., Little B.W., Emery E.S., Good P.S., Pendlebury W.W., Bradley W.G. Childhood giant axonal neuropathy. Case report and review of the literature. J. Neurol. Sci. 1987;82:205–228.
- Midroni G., Bilbao J.M. Butterworth-Heinmann; 1995. Biopsy Diagnosis of Peripheral Neuropathy; pp. 45–74.
- Clément N., Grieger J.C. Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol. Ther. Methods Clin. Dev. 2016;3:16002.
- Gray S.J., Choi V.W., Asokan A., Haberman R.A., McCown T.J., Samulski R.J. Production of recombinant adeno-associated viral vectors and use in in vitro and in vivo administration. Curr. Protoc. Neurosci. 2011;4 4.17.
- Karumuthil-Melethil S., Nagabhushan Kalburgi S., Thompson P., Tropak M., Kaytor M.D., Keimel J.G., Mark B.L., Mahuran D., Walia J.S., Gray S.J. Novel vector design and hexosaminidase variant enabling self-complementary adeno-associated virus for the treatment of Tay-Sachs disease. Hum. Gene Ther. 2016;27:509–521.
- Lawson S.N. The postnatal development of large light and small dark neurons in mouse dorsal root ganglia: a statistical analysis of cell numbers and size. J. Neurocytol. 1979;8:275–294.
- Karumuthil-Melethil S., Marshall M.S., Heindel C., Jakubauskas B., Bongarzone E.R., Gray S.J. Intrathecal administration of AAV/GALC vectors in 10-11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant. J. Neurosci. Res. 2016;94:1138–1151.
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