A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
10 03 2021
10 03 2021
Historique:
received:
20
02
2020
accepted:
19
02
2021
entrez:
11
3
2021
pubmed:
12
3
2021
medline:
13
7
2021
Statut:
ppublish
Résumé
Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.
Identifiants
pubmed: 33692132
pii: 13/584/eabb3945
doi: 10.1126/scitranslmed.abb3945
pmc: PMC8272521
mid: NIHMS1708902
pii:
doi:
Substances chimiques
BCL2L12 protein, human
0
Muscle Proteins
0
Nucleic Acids
0
Proto-Oncogene Proteins c-bcl-2
0
Gold
7440-57-5
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : S10 OD020118
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA216996
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208783
Pays : United States
Organisme : NLM NIH HHS
ID : R01 LM011297
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA151880
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA199091
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102669
Pays : United States
Informations de 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.
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