journal article·2024-01-30Open access

Neuronal Replenishment via Hydrogel-Rationed Delivery of Reprogramming Factors

Negar Mahmoudi, Yi Wang, Niamh Moriarty, Noorya Y. Ahmed, Nathalie Dehorter, Leszek Lisowski, Alan R. Harvey, Clare L. Parish, Richard J. Williams, David R. Nisbet

ACS Nano· Volume 18· Issue 4

Abstract

The central nervous system’s limited capacity for regeneration often leads to permanent neuronal loss following injury. Reprogramming resident reactive astrocytes into induced neurons at the site of injury is a promising strategy for neural repair, but challenges persist in stabilizing and accurately targeting viral vectors for transgene expression. In this study, we employed a bioinspired self-assembling peptide (SAP) hydrogel for the precise and controlled release of a hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1 neural reprogramming transgene. This method effectively mitigates the issues of high viral dosage at the target site, off-target delivery, and immunogenic reactions, enhancing the vector’s targeting and reprogramming efficiency. In vitro, this vector successfully induced neuron formation, as confirmed by morphological, histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation of reactive host astrocytes into induced neurons, concurrently reducing glial scarring. Our findings introduce a safe and effective method for treating central nervous system injuries, marking a significant advancement in regenerative neuroscience.
Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: RNA Interference and Gene Delivery · Virus-based gene therapy research · Nerve injury and regeneration

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Laboratory of Advanced Biomaterials, the John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia

ANU College of Engineering & Computer Science, Acton, ACT 2601, Australia

The Graeme Clark Institute, The University of Melbourne, Melbourne, VIC 3010, Australia

Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, VIC 3010, Australia

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia

The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia

The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia

Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia

Vector and Genome Engineering Facility, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia

Australian Genome Therapeutics Centre, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia

Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland

School of Human Sciences, The University of Western Australia, and Perron Institute for Neurological and Translational Science, Perth, WA 6009, Australia

IMPACT, School of Medicine, Deakin University, Geelong, VIC 3217, Australia

Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC 3010, Australia

Funding

National Health and Medical Research Council · Australian Research Council

References (85)

Show source-provided references
1. 10.1038/nature1762310.1038/nature17623 ↗
2. 10.1038/s41563-018-0083-810.1038/s41563-018-0083-8 ↗
3. 10.3389/fnins.2019.0079010.3389/fnins.2019.00790 ↗
4. 10.1186/s12929-018-0491-810.1186/s12929-018-0491-8 ↗
5. 10.1073/pnas.94.21.1166310.1073/pnas.94.21.11663 ↗
6. 10.4103/1673-5374.37134810.4103/1673-5374.371348 ↗
7. 10.1016/j.stem.2016.01.01210.1016/j.stem.2016.01.012 ↗
8. 10.1021/acschemneuro.8b0068410.1021/acschemneuro.8b00684 ↗
9. 10.1021/acschemneuro.8b0036510.1021/acschemneuro.8b00365 ↗
10. 10.1021/acsbiomaterials.6b0015610.1021/acsbiomaterials.6b00156 ↗
11. 10.1021/acsnano.1c1034410.1021/acsnano.1c10344 ↗
12. 10.1039/C6TB03130G10.1039/C6TB03130G ↗
13. 10.1016/j.ymthe.2019.09.00310.1016/j.ymthe.2019.09.003 ↗
14. Zhang L. · bioRxiv · 2018 · 261438
15. 10.1007/s12264-021-00751-310.1007/s12264-021-00751-3 ↗
16. 10.4103/1673-5374.29592510.4103/1673-5374.295925 ↗
17. 10.1007/s00401-009-0619-810.1007/s00401-009-0619-8 ↗
18. 10.1152/physrev.00041.201310.1152/physrev.00041.2013 ↗
19. 10.1113/JP28419710.1113/JP284197 ↗
20. 10.1038/s41467-021-27245-010.1038/s41467-021-27245-0 ↗
21. 10.1038/s41419-018-0891-410.1038/s41419-018-0891-4 ↗
22. 10.1101/2023.02.21.52945110.1101/2023.02.21.529451 ↗
23. 10.1128/jvi.63.9.3822-3828.198910.1128/jvi.63.9.3822-3828.1989 ↗
24. 10.4103/1673-5374.26518510.4103/1673-5374.265185 ↗
25. 10.3389/fnagi.2021.61285610.3389/fnagi.2021.612856 ↗
26. 10.1016/j.stem.2013.12.00110.1016/j.stem.2013.12.001 ↗
27. 10.1016/j.ebiom.2023.10453110.1016/j.ebiom.2023.104531 ↗
28. 10.1038/s41467-020-14855-310.1038/s41467-020-14855-3 ↗
29. 10.3389/fcell.2020.59188310.3389/fcell.2020.591883 ↗
30. 10.1038/8332410.1038/83324 ↗
31. 10.1016/j.ymthe.2019.12.01010.1016/j.ymthe.2019.12.010 ↗
32. 10.3390/v1102010210.3390/v11020102 ↗
33. 10.3390/brainsci1002011910.3390/brainsci10020119 ↗
34. 10.3389/fnins.2021.74772610.3389/fnins.2021.747726 ↗
35. 10.1080/14712598.2022.206073710.1080/14712598.2022.2060737 ↗
36. 10.1038/ncomms433810.1038/ncomms4338 ↗
37. 10.1038/s41556-020-0490-310.1038/s41556-020-0490-3 ↗
38. 10.1371/journal.pone.006768010.1371/journal.pone.0067680 ↗
39. 10.1016/j.cej.2023.14685710.1016/j.cej.2023.146857 ↗
40. 10.1038/s41434-019-0075-610.1038/s41434-019-0075-6 ↗
41. 10.1016/j.neuroscience.2010.08.03410.1016/j.neuroscience.2010.08.034 ↗
42. 10.1016/j.cell.2018.05.00210.1016/j.cell.2018.05.002 ↗
43. 10.1101/2020.08.16.25319510.1101/2020.08.16.253195 ↗
44. 10.1002/advs.20230370710.1002/advs.202303707 ↗
45. 10.1039/C4RA13266A10.1039/C4RA13266A ↗
46. 10.1073/pnas.060055910310.1073/pnas.0600559103 ↗
47. 10.1126/science.109378310.1126/science.1093783 ↗
48. 10.1016/j.semcancer.2005.05.00710.1016/j.semcancer.2005.05.007 ↗
49. 10.1073/pnas.92.14.634910.1073/pnas.92.14.6349 ↗
50. 10.1002/adbi.20180011310.1002/adbi.201800113 ↗
51. 10.1039/C4TB01391C10.1039/C4TB01391C ↗
52. 10.1016/j.celrep.2017.07.06910.1016/j.celrep.2017.07.069 ↗
53. 10.1016/j.actbio.2016.04.03810.1016/j.actbio.2016.04.038 ↗
54. 10.1002/adhm.20200123810.1002/adhm.202001238 ↗
55. 10.1007/s12274-015-0946-010.1007/s12274-015-0946-0 ↗
56. 10.1002/adma.20210875710.1002/adma.202108757 ↗
57. 10.1002/adfm.20190039010.1002/adfm.201900390 ↗
58. 10.1038/s41467-023-36133-810.1038/s41467-023-36133-8 ↗
59. 10.1002/adma.20180520910.1002/adma.201805209 ↗
60. 10.1038/s41573-019-0012-910.1038/s41573-019-0012-9 ↗
61. Deyle D. R. · Curr. Opin. Mol. Ther. · 2009 · 11 · 442
62. 10.1016/j.nbd.2015.05.00310.1016/j.nbd.2015.05.003 ↗
63. 10.1016/j.nano.2016.01.00910.1016/j.nano.2016.01.009 ↗
64. 10.1038/nnano.2008.37810.1038/nnano.2008.378 ↗
65. 10.1002/term.258210.1002/term.2582 ↗
66. 10.1002/adma.20070122110.1002/adma.200701221 ↗
67. 10.1039/c3sm27758e10.1039/c3sm27758e ↗
68. 10.1021/acsbiomaterials.1c0067510.1021/acsbiomaterials.1c00675 ↗
69. 10.1128/JVI.03017-1210.1128/JVI.03017-12 ↗
70. 10.1002/adfm.20230577110.1002/adfm.202305771 ↗
71. 10.1038/natrevmats.2016.7110.1038/natrevmats.2016.71 ↗
72. 10.1523/JNEUROSCI.23-07-02824.200310.1523/JNEUROSCI.23-07-02824.2003 ↗
73. 10.1046/j.1460-9568.2003.02727.x10.1046/j.1460-9568.2003.02727.x ↗
74. 10.1073/pnas.96.20.1161910.1073/pnas.96.20.11619 ↗
75. 10.1016/j.stem.2015.08.00210.1016/j.stem.2015.08.002 ↗
76. 10.1038/jcbfm.2009.25710.1038/jcbfm.2009.257 ↗
77. 10.1371/journal.pone.009700710.1371/journal.pone.0097007 ↗
78. 10.1002/cne.1087410.1002/cne.10874 ↗
79. 10.1016/S0896-6273(00)80778-310.1016/S0896-6273(00)80778-3 ↗
80. 10.1111/j.1460-9568.2004.03813.x10.1111/j.1460-9568.2004.03813.x ↗
81. 10.1016/j.cell.2021.09.00510.1016/j.cell.2021.09.005 ↗
82. 10.1073/pnas.191597411610.1073/pnas.1915974116 ↗
83. 10.1016/j.neuron.2011.05.00110.1016/j.neuron.2011.05.001 ↗
84. 10.1089/hum.2018.14410.1089/hum.2018.144 ↗
85. 10.1073/pnas.182100011610.1073/pnas.1821000116 ↗