CORVUS throws blood brain barrier a curve ball
brains of mice, which could herald a new dawn for the sufferers of
brain diseases such as Alzheimer's.
This latest research, described in the next issue of Nature uses a modified peptide, dubbed CORVUS, to enable small interfering RNA (siRNA) molecules to be delivered into the brains of mice suffering from fatal inflammation of the brain. One of the major challenges in treating neurological diseases is getting drugs across the blood-brain-barrier which is designed to prevent toxic molecules from passing into the brain. There is currently a huge need for new drugs to treat various 'neuronal' diseases, with over 18m people worldwide suffering from dementia (55 per cent suffering from Alzheimer's). A spokesperson for the Alzheimer's society has predicted this number will grow to over 34m by 2050. Researchers have tried various strategies to deliver drugs to the brain including osmotic or biochemical disrupting agents and even localised high intensity focussed ultrasound. The tagging of drugs to molecules that do pass through the barrier has also been utilised and this latest method takes a similar approach. According to the first author of the paper Dr Priti Kumar of the CBR Institute for Biomedical Research at the Harvard Medical School in Boston, US the market for this technology is enormous as it has the potential to deliver gene therapy agents and small molecule drugs into the brain avoiding many of the disadvantages observed using other approaches. The rabies virus glycoprotein (RVG) enables the Rabies virus to enter the brain and the researchers have modified this peptide to create the CORVUS delivery system which can carry molecules into the brain via a process known as transcytosis. "Transcytosis is a process by which molecules can get into a cell, pass through the cell, and get out. Molecules like insulin and transferrin have similarly been shown pass across the barrier to get into brain cells. We believe the RVG may do so by a similar process," said Kumar. However, unlike many of these approaches, rather than needing to covalently tag the drug molecules to the carrier, the researchers have built in a short positively charged peptide strand that electrostatically binds to negatively charged nucleic acids - such as those in siRNA. "The siRNA molecules that are held by electrostatic interaction appear to be released as they are functional in gene knockdown," said Kumar. Part of the RVG virus specifically binds to neuronal cells and allows the siRNA to be delivered to the brains of mice suffering from a fatal form of encephalitis - an acute inflammation of the brain commonly caused by viral infection. Treatment with the CORVUS-bound siRNA saved over 80 per cent of the mice, whereas the entirety of the non-treated animal group died. The researchers are currently doing more toxicology and bioavailability studies to enable an investigational new drug (IND) application to allow the system to go into clinical trials.
