Transvascular delivery of small interfering RNA to the central nervous system

By Priti Kumar, Haoquan Wu, J. McBride, K. Jung, M. Kim, B. Davidson, Sang Kyung Lee, P. Shankar, N. Manjunath. Nature, 2007

1,215 citations recorded by the source corpus.

A major impediment in the treatment of neurological diseases is the presence of the blood–brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood–brain barrier.

Subfields: Epidemiology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/47ef327207c9d8bff4cab233a516beefa9ad6397

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. R. Gabathuler
2. M. Wood

In Genetics

1. R. Gabathuler
2. F. Heitz
3. May C. Morris
4. G. Divita
5. B. Davidson

In Molecular Biology

1. P. McCray
2. R. Gabathuler
3. M. Wood
4. F. Heitz
5. May C. Morris
6. Claes Wahlestedt
7. M. Faghihi
8. P. Kenny

Citations in the corpus

• Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes (2011, methodology): “Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptid”
• The Emerging Field of RNA Nanotechnology (2010, neutral): “, nuclear membrane penetration, and blood–brain barrier passin”
• Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. (2010, methodology): “○ Kumar et al. (2007) demonstrated the transvascular delivery of siRNA to the CNS using a mixture of a peptide composed of 29 aa”
• siRNA vs. shRNA: similarities and differences. (2009, background): “as general discussions of organ and tissue specific RNAi delivery [138,158,159] may be found elsewhere.”
• Current prospects for RNA interference-based therapies (2011, background): “Other carriers for tissue-specific targeting include aptamers 53,54 , antibodies [55] [56] [57] [58] , peptides and proteins 52, 59 , and oligonucleotide agonists 36 .”
• The delivery of therapeutic oligonucleotides (2016, neutral): “Another interesting strategy involves use of a rabies virus peptide to target siRNA nanoparticles to neurons (81,82).”
• Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics (2009, positive): “…to be more appropriate for siRNA delivery and yield significant associated British Journal of Pharmacology (2009) 157 195–206 biological response (Simeoni et al., 2003; Kim et al., 2006; Veldhoen et al., 2006; Crombez et al., 2007; Kumar et al., 2007; Lundberg et al., 2007; Meade and Dowdy, 2007).”
• Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase (2008, background): “A recent technological breakthrough suggests that systemic administration of modified siRNA may cross the blood-brain barrier and thereby target RNA transcripts in the brai”