Silencing of genes by RNA interference (RNAi) can be triggered in cells by either DNA-directed (dd)RNAi (where silencing double stranded RNA molecules are produced in cells from a DNA construct), or short interfering (si)RNA (where double stranded RNA molecules which are synthesized in a laboratory are then delivered into cells externally).
Benitec has the predominant patent position in ddRNAi technology. It involves inserting a DNA construct into a cell, which then triggers the production of double stranded RNA (dsRNA) that is immediately cleaved into small interfering RNA (siRNA) by Dicer, a specific type of RNAse III, as part of the RNAi process. The siRNA then enters the cellular RNAi pathway and causes the destruction of the rogue gene or viral genomes.
In addition, from 2007-2010, Benitec supported a Phase I/II clinical trial in HIV of an RNA therapeutic, a component of which was a ddRNAi construct (a short hairpin targeted at the tat/rev gene in the HIV genome). The trial, which was conducted by researchers at the City of Hope in California, demonstrated the feasibility of the approach. The City of Hope have initiated a second study aimed at improving the efficiency of transfer of the material into the target CD34+ stem cells.
Benitec’s exclusive licensee, Tacere Therapeutics is developing a ddRNAi-based therapeutic for the treatment of Hepatitis C.Pain is one of the most common symptoms associated with cancer. 65% of all cancer patients experience pain.
Cancer can cause pain due to damage of tissues, bones, muscles or nerves.
Unfortunately, pain continues to be under-treated in cancer patients.
Opioid analgesics are the mainstay of nociceptive pain treatment for cancer patients with moderate-to-severe cancer pain in which tumour treatment (using radiation and/or chemotherapy) has failed. Oral administration for opioid treatment is the preferred pathway due to the convenience and lower price point, yet this method has a slower onset of action. Opioid delivery can also be accomplished via other routes including transdermal application, IV infusion or intraspinal infusion.
Neuropathic pain and chronic pain are often incapacitating and are resistant to conventional narcotic therapies. The search for novel treatments for this class of pain syndromes characterized by central sensitization has stimulated numerous investigations in both the basic science and clinical arena. Data indicate that a spinal enzyme contributes significantly to the development of central sensitization-mediated pain and suggests that it might be an important molecular target for the treatment of chronic pain of neuropathic origin. This presents a new opportunity to target genes in spinal cord neurons to ameliorate chronic pain using ddRNAi.
The aim of the project is to design a DNA construct expressing a short hairpin RNA targeted to one or more sequences of the gene for the enzyme in a preclinical model of pain. In theory, a single intrathecal injection which results in significant silencing of the enzyme gene could provide pain relief equivalent to that achievable by infusion of opioids. The target clinical group is terminally ill cancer patients initially, but could be extended to any group of patients suffering pain as a result of a terminal illness, including HIV/AIDS.
Lung cancer is the leading form of cancer worldwide in terms of incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. First line therapy for NSCLC includes a combination of a tubulin-binding agent (TBA) and DNA-damaging agents. The prognosis for patients with advanced NSCLC however remains dismal as the tumours rapidly become resistant to these drugs. Upregulation of a protein called beta III-tubulin is associated with clinical resistance to these drugs, as published in a Cancer Research paper in June 2010.
Benitec is collaborating with Children’s Cancer Institute Australia researchers at the University of New South Wales on a project aimed at developing a ddRNAi therapeutic targeting the beta III tubulin gene for drug resistant lung cancer.
More than 2,000 million people alive today have been infected with hepatitis B virus (HBV) at some time in their lives and of these about 350 million remain chronically infected and become carriers of the virus. In the USA alone there are over 1.25 million people living with the consequences of chronic active HBV, and over 60,000 new cases per year.
In September 2009, Benitec entered into an agreement with China-based Biomics Biotechnologies Co. Ltd. to collaborate on the development of a DNA directed (ddRNAi) therapeutic for the treatment of chronic hepatitis B virus (HBV) infection. Current therapies for chronic HBV infection (see below) have only limited inhibitory effects on viral gene expression and replication in the majority of chronically infected patients.
The application of ddRNAi technology to HBV infection has the potential to revolutionise the treatment of chronic hepatitis B. The aim of the collaborative research project is to directly target the activity of a specific HBV gene with minimum off-target effects on human genes. This could provide a unique strategy to address the current unmet clinical treatment needs for HBV infection.
Although numerous ddRNAi targets on the HBV genome could be chosen the Benitec/Biomics research team has selected a gene which has been shown to be critical for HBV survival based on pre-existing studies of the mode of action of a common drug used for treatment of this condition.
Until late 2010, Benitec supported the development of an RNA-based HIV/AIDS therapeutic, one component of which was an shRNA construct to tat/rev. This program was undertaken from 2007-2010 in collaboration with the City of Hope research hospital in Duarte, California. The product candidate was taken into a Phase I/II pilot human clinical trial funded by Benitec that produced promising interim results in terms of safety and proof of feasibility. The data was published in Science Translational Medicine in June 2010. Benitec believes these results justify the further development of a ddRNAi-based cell therapy platform for HIV. As a result, Benitec is currently seeking to partner this program to build on the initial promise. The City of Hope announced in March 2011 that they were initiating a second clinical trial building on the success of the first trial. The second study will examine an improved version of the treatment method.
