A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma

Priya Kumthekar*, Caroline H. Ko, Tatjana Paunesku, Karan Dixit, Adam M. Sonabend, Orin Bloch, Matthew Tate, Margaret Schwartz, Laura Zuckerman, Ray Lezon, Rimas V. Lukas, Borko Jovanovic, Kathleen McCortney, Howard Colman, Si Chen, Barry Lai, Olga Antipova, Junjing Deng, Luxi Li, Serena Tommasini-GhelfiLisa A. Hurley, Dusten Unruh, Nitya V. Sharma, Manoj Kandpal, Fotini M. Kouri, Ramana V. Davuluri, Daniel J. Brat, Miguel Muzzio, Mitchell Glass, Vinod Vijayakumar, Jeremy Heidel, Francis J. Giles, Ann K. Adams, C. David James, Gayle E. Woloschak, Craig Horbinski, Alexander H. Stegh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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-observedadverse- 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.

Original languageEnglish (US)
Article numbereabb3945
JournalScience translational medicine
Issue number584
StatePublished - Mar 10 2021

ASJC Scopus subject areas

  • Medicine(all)


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