Benitec's DdRNAi Targeting Fight Against HIV

| About: Benitec Biopharma (BTEBY)


HIV market to be worth $16B by 2019.

Calimmune, Johnson & Johnson and many universities pioneering pre-clinical and clinical studies using ddRNAi to treat HIV.

Benitec Biopharma has seminal ddRNAi patents.

One clinical trial completed and two more currently active.

A one-off treatment could provide a lifetime of protection against HIV/AIDS.


Human Immunodeficiency Virus (HIV) has been known about and researched for over thirty years. This article discusses one technology, ddRNAi, which several research teams are using in efforts to find a cure for the disease. This technology is possibly the single most explored technology in the fight against the disease and the seminal patents for the use of ddRNAi in humans are licensed exclusively to Benitec Biopharma (ASX: BLT, OTC: OTCPK:OTCPK:BTEBY).

It is estimated that the value of the HIV market will reach $16B by 2019.

What is HIV?

HIV is the virus which, if not treated, causes the on-set of AIDS (Acquired Immunodeficiency Syndrome). The virus is a lentivirus which means that it integrates its DNA with that of its host's in order to replicated and survive. Normally, the body's immune system would come to its defence when invaded by such a foreign body but HIV is designed to attack, conquer and thrive in the very immune system cells that are supposed to protect the host. Furthermore, the virus can hide away in viral reservoirs, latent and ready to re-emerge at any time. These factors make HIV a very significant adversary for even the best of our scientific minds to do battle with.

While treatment with antiviral drugs can now manage the disease, there is no known cure and the side effects of the antivirals can be severe.

In 2012, it was estimated that over thirty five million people were infected with the virus worldwide.

What is ddRNAi?

ddRNAi is a trade name used by Benitec Biopharma to describe a technology for silencing genes in the human body. The technology inserts a piece of synthetic DNA into the genome of targeted cells in the patient. The synthetic DNA is delivered to the appropriate cells in the patient via a vector. Once the DNA is incorporated into the genome, it continuously produces short hairpin RNA (shRNA), which, in turn, is processed by intracellular machinery until it interferes with the production of harmful proteins, thus silencing their production. More detailed information can be found here.

This technology is sometimes referred to as expressed shRNA and can be used not only to treat viral infections but also any indication that is caused by errant genes. Benitec's current pipeline includes indications such as Hepatitis C and B, cancer associated pain, Non-Small Cell Lung Cancer, Muscular Dystrophy and Age Related Macular Degeneration. The company has a number of seminal patents covering the use of ddRNAi in humans.

As the technology is DNA based it has the potential to provide a one-off treatment which will last the lifetime of the patient or, at the very least, the lifetime of the treated cells.

When heavyweight technology meets a heavyweight virus: ddRNAi v HIV

City of Hope and UC Davies

The first clinical trial for the application of ddRNAi against HIV was commenced by the City of Hope (NYSE:COH) in partnership with Benitec in 2007. This treatment involved harvesting stem cells from the patients, treating them with a ddRNAi molecule designed to interfere with HIV replication at three separate stages and then returning the cells to the patients. In this pilot trial the degree of ddRNAi transduction into the host stem cells genome was too low for the treatment to produce a therapeutic effect but it did prove to be safe and well tolerated. Dr John Rossi of City of Hope has commented that "one patient (continues to have) very robust expression of the ddRNAi".

Based in the information gathered through this trial the researchers at City of Hope continued the research under their own stem. It has taken a number of years but a new trial is now underway in which it is hoped that a higher degree of engraftment/transduction can be achieved.

This work was pioneered back in 2005/6 in collaboration with Dr. Joseph Anderson who has now moved from Colorado State University to University of California Davis and continues his work there. I understand that his research, which is very similar to that of CoH, has received FDA approval for a clinical trial but is yet to secure funding.


Using a different ddRNAi technique to prevent HIV attacking the immune system cells is Calimmune. This is a private company that has a license from Benitec Biopharma for the application of ddRNAi to treat HIV. The company, through its Chief Scientific Officer, Dr. Geoff Symonds, is working with other parties to improve and broaden the company's possible treatments for HIV.

HIV enters the host cells through a door (receptor) but the door needs to have a handle (co-receptor) before the virus can enter. Once the virus arrives at the door and grabs the handle, it enters the host cell via a process referred to as fusion. Some people lack the gene which produces the protein from which the handle is made. These people seem to be immune to HIV.

Calimmune has engineered a ddRNAi construct which silences the gene which produces the most common handle and therefore stops the virus from entering the host's cells. As a backup, Calimmune's treatment, Cal-1, also contains a fusion inhibitor so as to counter any HIV mutation which may try to use a different door handle. As this genetic variation is a replication of naturally occurring HIV immunity, the stopping of the production of this door handle is unlikely to have adverse consequences.

The ddRNAi construct is delivered to stem cells which continually divide and transform into HIV resistant immune system cells. This process turns the body's own processes into an anti-HIV drug factory; continually producing HIV resistant cells.

Mathematical modelling of Calimmune's method of treatment has revealed that the treatment could be therapeutic, over time, with relatively low levels of stem cell engraftment.

As with the CoH treatment, the ddRNAi transfection is done ex vivo. It is planned to be a single, one-off outpatient treatment, although annual, repeat treatments could be a possibility.

The company secured funding from the California Institute of Regenerative Medicine to start a clinical trial and is now dosing its second cohort of patients, with the Data Safety Monitoring Board giving the all-clear after safety results from the first cohort were reviewed.

Johnson & Johnson's involvement

Calimmune's Dr Symonds was previously employed by Johnson & Johnson (NYSE:JNJ) and J&J contributed to the early work on the application of ddRNAi to treat HIV. J&J has continued its involvement in research in to gene therapy and HIV through its partnership with the University of New South Wales and, according to this article, recently conducted a clinical trial in support of that research.

With such a close relationship between Calimmune, J&J and the UNSW one may be given to speculating that J&J may be tempted to offer to commercialise this research once it has proved efficacious in clinical trials. This would be a boon for Calimmune and therefore to Benitec also, through the existing licensing agreement.

University of New South Wales, Australia

As explained above, the UNSW is collaborating with both Calimmune and Johnson & Johnson on the application of ddRNAi to treat HIV. While the university continues to make a valuable contribution to these collaborations, it is also conducting its own research in to HIV using ddRNAi. In this research ddRNAi is shown to be efficacious in preventing the re-activation of latent HIV even when challenged with strong activating stimuli.

University of Amsterdam

Professor Berkhout and his team at the University of Amsterdam have been using ddRNAi to research HIV for many years. They have produced many papers on the subject, far too many to reference in this article. These papers cover different ways to use the technology to disrupt the HIV lifecycle. They have done a considerable amount of pre-clinical work, however, I believe that they lack the funding to take any of this research into the clinic.

What do the Russians and Chinese think?

The Russian Academy of Sciences has produced several papers on the application of ddRNAi to treat HIV. I am unaware of any clinical trials being conducted in Russia but the research is very consistent with that of the teams mentioned above in that it validates that, whichever approach is taken to disrupt HIV, multiple shRNA cassettes are required in the design of the ddRNAi construct. The ability of ddRNAi to accommodate this requirement for combining multiple targets into a single treatment is a major advantage of the technology.

Several universities and research institutions in China are also exploring ways to defeat HIV with ddRNAi.


The HIV market is a multibillion dollar opportunity. Many research teams around the world are using ddRNAi as the technology of choice in the fight against the disease. Some of these teams are already in clinical trials and more trials are planned. The technology is very flexible and lends itself to treating HIV. Treatments which use modified stem cells, such as Calimmune's treatment will, potentially, provide protection against the disease for the lifetime of the patient.

While Benitic Biopharma is no longer progressing its own HIV program, can certainly benefit from up front and royalty payments through its licensing agreement with Calimmune, if that treatment proves to be successful.

With all this research into HIV using this technology, when a functional cure is eventually found, there is a good chance that such a cure will be underpinned by ddRNAi.

Note: Most of these research teams use the technology under the "safe harbor" provisions of national and international patents. This article in no way implies that any of these teams will pay royalties or other payments to Benitec Biopharma for the use of ddRNAi. Only Calimmune has a current license to use the technology in the treatment of HIV.

The current trials of the application of ddRNAi involve ex vivo transfection of cells. In order for the majority of HIV sufferers to be treated the method of delivery will have to be improved and be more accessible.

Disclosure: The author is long BNIKF, BTEBY. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it. The author has no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: This article is not intended to be investment advice. Readers should do their own research.