Widespread and sustained target engagement in Huntington’s disease minipigs upon intrastriatal microRNA-based gene therapy
Targeting HTT in pigs
Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by mutated huntingtin (HTT) gene. Reducing the expression of the aberrant HTT has been shown to be effective in preclinical models. Now, Vallès et al. evaluated the effects of an adeno-associated viral vector (AAV)–mediated strategy delivering microRNA (miRNA) targeting human mutant HTT (mHTT) in a pig model of HD that closely resembles the human condition. Intracerebral delivery of the miRNA into the striatum resulted in widespread distribution and reduced mHTT for up to a year after injection. The results suggest that the approach could be effective in patients with HD.
Abstract
Huntingtin (HTT)–lowering therapies hold promise to slow down neurodegeneration in Huntington’s disease (HD). Here, we assessed the translatability and long-term durability of recombinant adeno-associated viral vector serotype 5 expressing a microRNA targeting human HTT (rAAV5-miHTT) administered by magnetic resonance imaging–guided convention-enhanced delivery in transgenic HD minipigs. rAAV5-miHTT (1.2 × 1013 vector genome (VG) copies per brain) was successfully administered into the striatum (bilaterally in caudate and putamen), using age-matched untreated animals as controls. Widespread brain biodistribution of vector DNA was observed, with the highest concentration in target (striatal) regions, thalamus, and cortical regions. Vector DNA presence and transgene expression were similar at 6 and 12 months after administration. Expression of miHTT strongly correlated with vector DNA, with a corresponding reduction of mutant HTT (mHTT) protein of more than 75% in injected areas, and 30 to 50% lowering in distal regions. Translational pharmacokinetic and pharmacodynamic measures in cerebrospinal fluid (CSF) were largely in line with the effects observed in the brain. CSF miHTT expression was detected up to 12 months, with CSF mHTT protein lowering of 25 to 30% at 6 and 12 months after dosing. This study demonstrates widespread biodistribution, strong and durable efficiency of rAAV5-miHTT in disease-relevant regions in a large brain, and the potential of using CSF analysis to determine vector expression and efficacy in the clinic.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
Summary
Fig. S1. Design and mechanism of action of rAAV5-miHTT leading to HTT lowering in the cell.
Fig. S2. Brain dissection scheme for bioanalytics.
Fig. S3. VG copies in deep brain regions of tgHD minipigs at 6 and 12 months after rAAV5-miHTT administration in the caudate and putamen.
Fig. S4. Correlation between miHTT expression and mHTT protein lowering (as percentage from control), 12 months after rAAV5-miHTT administration.
Fig. S5. HTT protein concentrations in the CSF of tgHD minipigs increase with age, as determined by two independent immunoassays.
Fig. S6. No differences in CSF NFL between wild-type and tgHD minipigs up to 4 years of age.
Table S1. Statistical analysis of mHTT in the CSF of tgHD minipigs (control versus treated).
Table S2. Experimental approach for intrastriatal miRNA-based gene therapy in tgHD minipigs.
Data file S1. Raw data (provided as supplementary Excel file).
Resources
REFERENCES AND NOTES
1
G. P. Bates, R. Dorsey, J. F. Gusella, M. R. Hayden, C. Kay, B. R. Leavitt, M. Nance, C. A. Ross, R. I. Scahill, R. Wetzel, E. J. Wild, S. J. Tabrizi, Huntington disease. Nat. Rev. Dis. Primers 1, 15005 (2015).
2
H. J. Waldvogel, E. H. Kim, L. J. Tippett, J.-P. G. Vonsattel, R. L. M. Faull, The neuropathology of Huntington’s disease. Curr. Top. Behav. Neurosci. 22, 33–80 (2015).
3
K. J. Wyant, A. J. Ridder, P. Dayalu, Huntington’s disease-update on treatments. Curr. Neurol. Neurosci. Rep. 17, 33 (2017).
4
C. A. Ross, E. H. Aylward, E. J. Wild, D. R. Langbehn, J. D. Long, J. H. Warner, R. I. Scahill, B. R. Leavitt, J. C. Stout, J. S. Paulsen, R. Reilmann, P. G. Unschuld, A. Wexler, R. L. Margolis, S. J. Tabrizi, Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10, 204–216 (2014).
5
S. J. Tabrizi, R. Ghosh, B. R. Leavitt, Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 102, 899 (2019).
6
P. McColgan, S. J. Tabrizi, Huntington’s disease: A clinical review. Eur. J. Neurol. 25, 24–34 (2018).
7
S. J. Tabrizi, B. R. Leavitt, G. B. Landwehrmeyer, E. J. Wild, C. Saft, R. A. Barker, N. F. Blair, D. Craufurd, J. Priller, H. Rickards, A. Rosser, H. B. Kordasiewicz, C. Czech, E. E. Swayze, D. A. Norris, T. Baumann, I. Gerlach, S. A. Schobel, E. Paz, A. V. Smith, C. F. Bennett, R. M. Lane; Phase 1–2a IONIS-HTTRx Study Site Teams, Targeting huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316 (2019).
8
H. B. Kordasiewicz, L. M. Stanek, E. V. Wancewicz, C. Mazur, M. M. McAlonis, K. A. Pytel, J. W. Artates, A. Weiss, S. H. Cheng, L. S. Shihabuddin, G. Hung, C. F. Bennett, D. W. Cleveland, Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012).
9
J. F. Alterman, B. M. D. C. Godinho, M. R. Hassler, C. M. Ferguson, D. Echeverria, E. Sapp, R. A. Haraszti, A. H. Coles, F. Conroy, R. Miller, L. Roux, P. Yan, E. G. Knox, A. A. Turanov, R. M. King, G. Gernoux, C. Mueller, H. L. Gray-Edwards, R. P. Moser, N. C. Bishop, S. M. Jaber, M. J. Gounis, M. Sena-Esteves, A. A. Pai, M. DiFiglia, N. Aronin, A. Khvorova, A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 37, 884–894 (2019).
10
S. R. Choudhury, E. Hudry, C. A. Maguire, M. Sena-Esteves, X. O. Breakefield, P. Grandi, Viral vectors for therapy of neurologic diseases. Neuropharmacology 120, 63–80 (2017).
11
S. Ingusci, G. Verlengia, M. Soukupova, S. Zucchini, M. Simonato, Gene therapy tools for brain diseases. Front. Pharmacol. 10, 724 (2019).
12
Y. Chu, R. T. Bartus, F. P. Manfredsson, C. W. Olanow, J. H. Kordower, Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson’s disease. Brain 143, 960–975 (2020).
13
B. L. Davidson, C. S. Stein, J. A. Heth, I. Martins, R. M. Kotin, T. A. Derksen, J. Zabner, A. Ghodsi, J. A. Chiorini, 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. 97, 3428–3432 (2000).
14
N. S. Caron, A. L. Southwell, C. C. Brouwers, L. D. Cengio, Y. Xie, H. F. Black, L. M. Anderson, S. Ko, X. Zhu, S. J. van Deventer, M. M. Evers, P. Konstantinova, M. R. Hayden, Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease. Nucleic Acids Res. 48, 36–54 (2020).
15
J. Miniarikova, M. M. Evers, P. Konstantinova, Translation of microRNA-based huntingtin-lowering therapies from preclinical studies to the clinic. Mol. Ther. 26, 947–962 (2018).
16
L. M. Stanek, J. Bu, L. S. Shihabuddin, Astrocyte transduction is required for rescue of behavioral phenotypes in the YAC128 mouse model with AAV-RNAi mediated HTT lowering therapeutics. Neurobiol. Dis. 129, 29–37 (2019).
17
L. M. Stanek, S. P. Sardi, B. Mastis, A. R. Richards, C. M. Treleaven, T. Taksir, K. Misra, S. H. Cheng, L. S. Shihabuddin, Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum. Gene Ther. 25, 461–474 (2014).
18
E. L. Pfister, K. O. Chase, H. Sun, L. A. Kennington, F. Conroy, E. Johnson, R. Miller, F. Borel, N. Aronin, C. Mueller, Safe and efficient silencing with a Pol II, but not a Pol lII, promoter expressing an artificial miRNA targeting human huntingtin. Mol. Ther. Nucleic Acids 7, 324–334 (2017).
19
B. Zeitler, S. Froelich, K. Marlen, D. A. Shivak, Q. Yu, D. Li, J. R. Pearl, J. C. Miller, L. Zhang, D. E. Paschon, S. J. Hinkley, I. Ankoudinova, S. Lam, D. Guschin, L. Kopan, J. M. Cherone, H.-O. B. Nguyen, G. Qiao, Y. Ataei, M. C. Mendel, R. Amora, R. Surosky, J. Laganiere, B. J. Vu, A. Narayanan, Y. Sedaghat, K. Tillack, C. Thiede, A. Gärtner, S. Kwak, J. Bard, L. Mrzljak, L. Park, T. Heikkinen, K. K. Lehtimäki, M. M. Svedberg, J. Häggkvist, L. Tari, M. Tóth, A. Varrone, C. Halldin, A. E. Kudwa, S. Ramboz, M. Day, J. Kondapalli, D. J. Surmeier, F. D. Urnov, P. D. Gregory, E. J. Rebar, I. Muñoz-Sanjuán, H. S. Zhang, Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 25, 1131–1142 (2019).
20
J. Miniarikova, I. Zanella, A. Huseinovic, T. van der Zon, E. Hanemaaijer, R. Martier, A. Koornneef, A. L. Southwell, M. R. Hayden, S. J. van Deventer, H. Petry, P. Konstantinova, Design, characterization, and lead selection of therapeutic miRNAs targeting huntingtin for development of gene therapy for Huntington’s disease. Mol. Ther. Nucleic Acids 5, e297 (2016).
21
J. Miniarikova, V. Zimmer, R. Martier, C. C. Brouwers, C. Pythoud, K. Richetin, M. Rey, J. Lubelski, M. M. Evers, S. J. van Deventer, H. Petry, N. Déglon, P. Konstantinova, AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther. 24, 630–639 (2017).
22
E. A. Spronck, C. C. Brouwers, A. Vallès, M. de Haan, H. Petry, S. J. van Deventer, P. Konstantinova, M. M. Evers, AAV5-miHTT gene therapy demonstrates sustained huntingtin lowering and functional improvement in Huntington disease mouse models. Mol. Ther. Methods Clin. Dev. 13, 334–343 (2019).
23
M. M. Evers, J. Miniarikova, S. Juhas, A. Vallès, B. Bohuslavova, J. Juhasova, H. K. Skalnikova, P. Vodicka, I. Valekova, C. Brouwers, B. Blits, J. Lubelski, H. Kovarova, Z. Ellederova, S. J. van Deventer, H. Petry, J. Motlik, P. Konstantinova, AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington’s disease minipig model. Mol. Ther. 26, 2163–2177 (2018).
24
S. Keskin, C. C. Brouwers, M. Sogorb-Gonzalez, R. Martier, J. A. Depla, A. Vallès, S. J. van Deventer, P. Konstantinova, M. M. Evers, AAV5-miHTT lowers huntingtin mRNA and protein without off-target effects in patient-derived neuronal cultures and astrocytes. Mol. Ther. Methods Clin. Dev. 15, 275–284 (2019).
25
N. M. Lind, A. Moustgaard, J. Jelsing, G. Vajta, P. Cumming, A. K. Hansen, The use of pigs in neuroscience: Modeling brain disorders. Neurosci. Biobehav. Rev. 31, 728–751 (2007).
26
M. Baxa, M. Hruska-Plochan, S. Juhas, P. Vodicka, A. Pavlok, J. Juhasova, A. Miyanohara, T. Nejime, J. Klima, M. Macakova, S. Marsala, A. Weiss, S. Kubickova, P. Musilova, R. Vrtel, E. M. Sontag, L. M. Thompson, J. Schier, H. Hansikova, D. S. Howland, E. Cattaneo, M. DiFiglia, M. Marsala, J. Motlik, A transgenic minipig model of Huntington’s disease. J. Huntingtons Dis. 2, 47–68 (2013).
27
T. Ardan, M. Baxa, B. Levinská, M. Sedláčková, T. D. Nguyen, J. Klima, S. Juhás, J. Juhásová, P. Šmatlíková, P. Vochozková, J. Motlík, Z. Ellederová, Transgenic minipig model of Huntington’s disease exhibiting gradually progressing neurodegeneration. Dis. Model. Mech. 13, dmm041319 (2019).
28
J. Krizova, H. Stufkova, M. Rodinova, M. Macakova, B. Bohuslavova, D. Vidinska, J. Klima, Z. Ellederova, A. Pavlok, D. S. Howland, J. Zeman, J. Motlik, H. Hansikova, Mitochondrial metabolism in a large-animal model of Huntington disease: The hunt for biomarkers in the spermatozoa of presymptomatic minipigs. Neurodegener. Dis. 17, 213–226 (2017).
29
M. Rodinova, J. Krizova, H. Stufkova, B. Bohuslavova, G. Askeland, Z. Dosoudilova, S. Juhas, J. Juhasova, Z. Ellederova, J. Zeman, L. Eide, J. Motlik, H. Hansikova, Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington’s disease. Dis. Model. Mech. 12, dmm038737 (2019).
30
D. Vidinská, P. Vochozková, P. Šmatlíková, T. Ardan, J. Klíma, S. Juhás, J. Juhásová, B. Bohuslavová, M. Baxa, I. Valeková, J. Motlík, Z. Ellederová, Gradual phenotype development in Huntington disease transgenic minipig model at 24 months of age. Neurodegener. Dis. 18, 107–119 (2018).
31
M. Baxa, B. Levinska, M. Skrivankova, M. Pokorny, J. Juhasova, J. Klima, J. Klempir, J. Motlík, S. Juhas, Z. Ellederova, Longitudinal study revealed motor, cognitive and behavioral decline in transgenic minipig model of Huntington’s disease. Dis. Model. Mech. 13, dmm041293 (2019).
32
F. B. Rodrigues, L. M. Byrne, E. J. Wild, Biofluid biomarkers in Huntington’s disease. Methods Mol. Biol. 1780, 329–396 (2018).
33
V. Fodale, R. Boggio, M. Daldin, C. Cariulo, M. C. Spiezia, L. M. Byrne, B. R. Leavitt, E. J. Wild, D. Macdonald, A. Weiss, A. Bresciani, Validation of ultrasensitive mutant huntingtin detection in human cerebrospinal fluid by single molecule counting immunoassay. J. Huntingtons Dis. 6, 349–361 (2017).
34
E. J. Wild, R. Boggio, D. Langbehn, N. Robertson, S. Haider, J. R. C. Miller, H. Zetterberg, B. R. Leavitt, R. Kuhn, S. J. Tabrizi, D. Macdonald, A. Weiss, Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J. Clin. Invest. 125, 1979–1986 (2015).
35
M. M. J. van den Berg, J. Krauskopf, J. G. Ramaekers, J. C. S. Kleinjans, J. Prickaerts, J. J. Briedé, Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders. Prog. Neurobiol. 185, 101732 (2020).
36
L. M. Byrne, F. B. Rodrigues, E. B. Johnson, P. A. Wijeratne, E. De Vita, D. C. Alexander, G. Palermo, C. Czech, S. Schobel, R. I. Scahill, A. Heslegrave, H. Zetterberg, E. J. Wild, Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease. Sci. Transl. Med. 10, eaat7108 (2018).
37
R. H. Bobo, D. W. Laske, A. Akbasak, P. F. Morrison, R. L. Dedrick, E. H. Oldfield, Convection-enhanced delivery of macromolecules in the brain. Proc. Natl. Acad. Sci. U.S.A. 91, 2076–2080 (1994).
38
N. U. Barua, M. Woolley, A. S. Bienemann, D. Johnson, M. J. Wyatt, C. Irving, O. Lewis, E. Castrique, S. S. Gill, Convection-enhanced delivery of AAV2 in white matter—A novel method for gene delivery to cerebral cortex. J. Neurosci. Methods 220, 1–8 (2013).
39
P. Dietrich, I. M. Johnson, S. Alli, I. Dragatsis, Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis. PLOS Genet. 13, e1006846 (2017).
40
L. Samaranch, B. Blits, W. San Sebastian, P. Hadaczek, J. Bringas, V. Sudhakar, M. Macayan, P. J. Pivirotto, H. Petry, K. S. Bankiewicz, MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther. 24, 253–261 (2017).
41
M. E. Emborg, S. A. Hurley, V. Joers, D. P. M. Tromp, C. R. Swanson, S. Ohshima-Hosoyama, V. Bondarenko, K. Cummisford, M. Sonnemans, S. Hermening, B. Blits, A. L. Alexander, Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery. Stereotact. Funct. Neurosurg. 92, 182–194 (2014).
42
E. A. Markakis, K. P. Vives, J. Bober, S. Leichtle, C. Leranth, J. Beecham, J. D. Elsworth, R. H. Roth, R. J. Samulski, D. E. Redmond Jr., Comparative transduction efficiency of AAV vector serotypes 1–6 in the substantia nigra and striatum of the primate brain. Mol. Ther. 18, 588–593 (2010).
43
A. Gerits, P. Vancraeyenest, S. Vreysen, M.-E. Laramée, A. Michiels, R. Gijsbers, C. Van den Haute, L. Moons, Z. Debyser, V. Baekelandt, L. Arckens, W. Vanduffel, Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex. Neurophotonics 2, 031209 (2015).
44
I. Diester, M. T. Kaufman, M. Mogri, R. Pashaie, W. Goo, O. Yizhar, C. Ramakrishnan, K. Deisseroth, K. V. Shenoy, An optogenetic toolbox designed for primates. Nat. Neurosci. 14, 387–397 (2011).
45
M.-A. Colle, F. Piguet, L. Bertrand, S. Raoul, I. Bieche, L. Dubreil, D. Sloothaak, C. Bouquet, P. Moullier, P. Aubourg, Y. Cherel, N. Cartier, C. Sevin, Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum. Mol. Genet. 19, 147–158 (2010).
46
J.-M. Taymans, L. H. Vandenberghe, C. Van Den Haute, I. Thiry, C. M. Deroose, L. Mortelmans, J. M. Wilson, Z. Debyser, V. Baekelandt, Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 18, 195–206 (2007).
47
I. Scheyltjens, M.-E. Laramée, C. Van den Haute, R. Gijsbers, Z. Debyser, V. Baekelandt, S. Vreysen, L. Arckens, Evaluation of the expression pattern of rAAV2/1, 2/5, 2/7, 2/8, and 2/9 serotypes with different promoters in the mouse visual cortex. J. Comp. Neurol. 523, 2019–2042 (2015).
48
B. E. Deverman, B. M. Ravina, K. S. Bankiewicz, S. M. Paul, D. W. Y. Sah, Gene therapy for neurological disorders: Progress and prospects. Nat. Rev. Drug Discov. 17, 641–659 (2018).
49
A. M. Dudek, N. Zabaleta, E. Zinn, S. Pillay, J. Zengel, C. Porter, J. S. Franceschini, R. Estelien, J. E. Carette, G. L. Zhou, L. H. Vandenberghe, GPR108 is a highly conserved AAV entry factor. Mol. Ther. 28, 367–381 (2020).
50
C. Burger, O. S. Gorbatyuk, M. J. Velardo, C. S. Peden, P. Williams, S. Zolotukhin, P. J. Reier, R. J. Mandel, N. Muzyczka, Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol. Ther. 10, 302–317 (2004).
51
M. Gray, Astrocytes in Huntington’s disease. Adv. Exp. Med. Biol. 1175, 355–381 (2019).
52
J. Guduric-Fuchs, A. O’Connor, B. Camp, C. L. O’Neill, R. J. Medina, D. A. Simpson, Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics 13, 357 (2012).
53
R. Reshke, J. A. Taylor, A. Savard, H. Guo, L. H. Rhym, P. S. Kowalski, M. T. Trung, C. Campbell, W. Little, D. G. Anderson, D. Gibbings, Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone. Nat. Biomed. Eng. 4, 52–68 (2020).
54
M. S. Keiser, H. B. Kordasiewicz, J. L. McBride, Gene suppression strategies for dominantly inherited neurodegenerative diseases: Lessons from Huntington’s disease and spinocerebellar ataxia. Hum. Mol. Genet. 25, R53–R64 (2016).
55
E. L. Pfister, N. DiNardo, E. Mondo, F. Borel, F. Conroy, C. Fraser, G. Gernoux, X. Han, D. Hu, E. Johnson, L. Kennington, P. Liu, S. J. Reid, E. Sapp, P. Vodicka, T. Kuchel, A. J. Morton, D. Howland, R. Moser, M. Sena-Esteves, G. Gao, C. Mueller, M. DiFiglia, N. Aronin, Artificial miRNAs reduce human mutant huntingtin throughout the striatum in a transgenic sheep model of Huntington’s disease. Hum. Gene Ther. 29, 663–673 (2018).
56
J. C. Jacobsen, C. S. Bawden, S. R. Rudiger, C. J. McLaughlan, S. J. Reid, H. J. Waldvogel, M. E. MacDonald, J. F. Gusella, S. K. Walker, J. M. Kelly, G. C. Webb, R. L. M. Faull, M. I. Rees, R. G. Snell, An ovine transgenic Huntington’s disease model. Hum. Mol. Genet. 19, 1873–1882 (2010).
57
J. L. McBride, M. R. Pitzer, R. L. Boudreau, B. Dufour, T. Hobbs, S. R. Ojeda, B. L. Davidson, Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol. Ther. 19, 2152–2162 (2011).
58
R. Grondin, M. D. Kaytor, Y. Ai, P. T. Nelson, D. R. Thakker, J. Heisel, M. R. Weatherspoon, J. L. Blum, E. N. Burright, Z. Zhang, W. F. Kaemmerer, Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135, 1197–1209 (2012).
59
S. E. Leff, S. K. Spratt, R. O. Snyder, R. J. Mandel, Long-term restoration of striatal L-aromatic amino acid decarboxylase activity using recombinant adeno-associated viral vector gene transfer in a rodent model of Parkinson’s disease. Neuroscience 92, 185–196 (1999).
60
D. Sondhi, D. A. Peterson, E. L. Giannaris, C. T. Sanders, B. S. Mendez, B. De, A. B. Rostkowski, B. Blanchard, K. Bjugstad, J. R. Sladek Jr., D. E. Redmond Jr., P. L. Leopold, S. M. Kaminsky, N. R. Hackett, R. G. Crystal, AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL. Gene Ther. 12, 1618–1632 (2005).
61
P. Hadaczek, J. L. Eberling, P. Pivirotto, J. Bringas, J. Forsayeth, K. S. Bankiewicz, Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol. Ther. 18, 1458–1461 (2010).
62
G. Mittermeyer, C. W. Christine, K. H. Rosenbluth, S. L. Baker, P. Starr, P. Larson, P. L. Kaplan, J. Forsayeth, M. J. Aminoff, K. S. Bankiewicz, Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum. Gene Ther. 23, 377–381 (2012).
63
A. L. Southwell, S. E. P. Smith, T. R. Davis, N. S. Caron, E. B. Villanueva, Y. Xie, J. A. Collins, M. L. Ye, A. Sturrock, B. R. Leavitt, A. G. Schrum, M. R. Hayden, Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci. Rep. 5, 12166 (2015).
64
R. Constantinescu, M. Romer, D. Oakes, L. Rosengren, K. Kieburtz, Levels of the light subunit of neurofilament triplet protein in cerebrospinal fluid in Huntington’s disease. Parkinsonism Relat. Disord. 15, 245–248 (2009).
65
L. M. Byrne, F. B. Rodrigues, K. Blennow, A. Durr, B. R. Leavitt, R. A. C. Roos, R. I. Scahill, S. J. Tabrizi, H. Zetterberg, D. Langbehn, E. J. Wild, Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: A retrospective cohort analysis. Lancet Neurol. 16, 601–609 (2017).
66
J. Kuhle, G. Disanto, J. Lorscheider, T. Stites, Y. Chen, F. Dahlke, G. Francis, A. Shrinivasan, E.-W. Radue, G. Giovannoni, L. Kappos, Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology 84, 1639–1643 (2015).
67
Å. Mellgren, R. W. Price, L. Hagberg, L. Rosengren, B. J. Brew, M. Gisslén, Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 69, 1536–1541 (2007).
68
B. Olsson, L. Alberg, N. C. Cullen, E. Michael, L. Wahlgren, A.-K. Kroksmark, K. Rostasy, K. Blennow, H. Zetterberg, M. Tulinius, NFL is a marker of treatment response in children with SMA treated with nusinersen. J. Neurol. 266, 2129–2136 (2019).
69
J. Kuhle, H. Kropshofer, D. A. Haering, U. Kundu, R. Meinert, C. Barro, F. Dahlke, D. Tomic, D. Leppert, L. Kappos, Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology 92, e1007–e1015 (2019).
70
S. A. Schobel (2020).
71
R. Constantinescu, B. Holmberg, L. Rosengren, O. Corneliusson, B. Johnels, H. Zetterberg, Light subunit of neurofilament triplet protein in the cerebrospinal fluid after subthalamic nucleus stimulation for Parkinson’s disease. Acta Neurol. Scand. 124, 206–210 (2011).
72
F. Saudou, S. Humbert, The biology of huntingtin. Neuron 89, 910–926 (2016).
73
A. Majowicz, D. Salas, N. Zabaleta, E. Rodríguez-Garcia, G. González-Aseguinolaza, H. Petry, V. Ferreira, Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5ch and AAV1. Mol. Ther. 25, 1831–1842 (2017).
74
M. Urabe, C. Ding, R. M. Kotin, Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum. Gene Ther. 13, 1935–1943 (2002).
75
C. Unzu, S. Hervás-Stubbs, A. Sampedro, I. Mauleón, U. Mancheño, C. Alfaro, R. E. de Salamanca, A. Benito, S. G. Beattie, H. Petry, J. Prieto, I. Melero, A. Fontanellas, Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J. Transl. Med. 10, 122 (2012).
(0)eLetters
eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed. Please read our Terms of Service before submitting your own eLetter.
Log In to Submit a ResponseNo eLetters have been published for this article yet.
Information & Authors
Information
Published In
Science Translational Medicine
Volume 13 | Issue 588
April 2021
April 2021
Copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 25 March 2020
Accepted: 9 January 2021
Acknowledgments
We would like to thank O. Lewis, M. Wooley, and D. Johnson from Renishaw for valuable support during the CED surgical procedure. We are grateful to the teams of Process Development and Analytical Development at uniQure for the production and characterization of rAAV5-miHTT and to E. Sawyer and E. Broug for critically reading the manuscript. OCS Life Sciences provided support with statistical analysis of CSF mHTT. We are also grateful for the support from the CHDI Foundation, in particular, D. Macdonald and D. Howland. Funding: Part of this work was supported by PIGMOD Center’s sustainability program: National Sustainability Programme, project number LO1609 (Czech Ministry of Education, Youth and Sports) to J.M. Author contributions: Conceptualization: A.V., M.M.E., B. Blits, J.M., Z.E., H.P., S.v.D., and P.K. Surgery: B. Bohuslavova, R.L., D.U., Z.S., M.C., B. Blits, Z.E., and J.M. Sample collection: A.V., M.S.-G., C.B., L.P., J.K., B. Bohuslavova, and Z.E. Molecular and data analyses: A.V., M.M.E., A.S., M.S.-G., C.B., C.V.-T., S.A.-B., L.P., R.P., V.F., and A.B. Formal analysis: A.V. and M.M.E. Writing: A.V. Funding acquisition: Z.E., J.M., H.P., S.v.D., and P.K. Supervision: A.V., M.M.E., Z.E., J.M., and P.K. Competing interests: A.V., M.M.E., A.S., M.S.-G., C.B., C.V.-T., S.A.-B., L.P., H.P., S.v.D., and P.K. are employees and shareholders at uniQure; Z.E., J.M., and PIGMOD have a collaborative agreement with uniQure. Filed patent applications pertaining to the results presented in this paper include the following: RNAi-induced huntingtin gene suppression (WO2016/102664, resulting in at least US 10,174,321, US 10,767,180, and EP 3237618B1), A companion diagnostic to monitor the effects of gene therapy (PCT/EP2019/081759), Method and means to deliver miRNA to target cells (PCT/EP2019/081822), and Targeting misspliced transcripts in genetic disorders (PCT/EP2020/075871); the latter three have not yet been published. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials, and, if required, materials may be available subject to at least a material transfer agreement.
Authors
Funding Information
National Sustainability Programme (Czech Ministry of Education, Youth and Sports): project number LO1609
Metrics & Citations
Metrics
Article Usage
Altmetrics
Citations
Export citation
Select the format you want to export the citation of this publication.
Cited by
- Neuronal and astrocytic contributions to Huntington’s disease dissected with zinc finger protein transcriptional repressors, Cell Reports, 42, 1, (111953), (2023).https://doi.org/10.1016/j.celrep.2022.111953
- Early detection of exon 1 huntingtin aggregation in zQ175 brains by molecular and histological approaches, Brain Communications, 5, 1, (2023).https://doi.org/10.1093/braincomms/fcad010
- Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease, Nature Biomedical Engineering, (2023).https://doi.org/10.1038/s41551-023-01007-3
- Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig, Frontiers in Cell and Developmental Biology, 10, (2023).https://doi.org/10.3389/fcell.2022.1115348
- Targeted gene silencing in the nervous system with CRISPR-Cas13, Science Advances, 8, 3, (2022)./doi/10.1126/sciadv.abk2485
- Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease, Science Translational Medicine, 14, 630, (2022)./doi/10.1126/scitranslmed.abm3682
- Role of autophagy and transcriptome regulation in acute brain injury, Experimental Neurology, 352, (114032), (2022).https://doi.org/10.1016/j.expneurol.2022.114032
- Mitochondrial organization and structure are compromised in fibroblasts from patients with Huntington’s disease, Ultrastructural Pathology, 46, 5, (462-475), (2022).https://doi.org/10.1080/01913123.2022.2100951
- Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice, Neurobiology of Disease, 166, (105652), (2022).https://doi.org/10.1016/j.nbd.2022.105652
- Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities, The Lancet Neurology, 21, 7, (645-658), (2022).https://doi.org/10.1016/S1474-4422(22)00121-1
- See more
Loading...
View Options
Check Access
Log in to view the full text
AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.
- Become a AAAS Member
- Activate your AAAS ID
- Purchase Access to Other Journals in the Science Family
- Account Help
Log in via OpenAthens.
Log in via Shibboleth.
More options
Register for free to read this article
As a service to the community, this article is available for free. Login or register for free to read this article.