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Flicking the switch

Therapeutics that turn off mutant genes could light the way in fighting diseases

An on/off switchImagine being able to turn off a gene like turning off a light switch. Flick the switch and the mutant gene that causes Huntington's disease, for example, no longer produces the Huntington protein responsible for that disease.

Extend this to stopping genes responsible for viral replication or cancer proliferation and you have a vision of a powerful technique with the potential to treat a multitude of diseases. The possibility of being able to 'flick the switch' on Huntington's disease may not be a reality today, but recent developments in the field of RNA interference suggest that the idea is far from being science fiction.

In 1998, a study published in Nature explained the mechanism by which a gene is silenced. Researchers, Andrew Fire and Craig Mello, discovered that injecting double-stranded RNA into the C. elegans worm resulted in reduced expression ie silencing of genes with a matching nucleotide sequence. Fire and Mello received the Nobel Prize in physiology/medicine in 2006 for their discovery of this process termed RNA interference (RNAi).

RNAi is a naturally occurring phenomenon for regulating gene expression and may protect the genome against viruses and mobile or 'jumping' genes. The natural process involves cleaving long double-stranded RNA molecules into short 21-25 base-pair fragments, which act as guides to prevent protein production from RNA. These short fragments, known as short interfering RNAs (siRNA), can also be chemically synthesised and delivered to cells, triggering the silencing of a particular gene.

The potential for harnessing this phenomenon in order to develop pharmaceuticals is exciting and a number of companies have been set up to develop interfering RNA products.

Biotechnology companies such as Alnylam, Sirna, Quark, Silence and Isis are leading the field, but big pharma is also jumping on the bandwagon. Several companies including Pfizer, Abbott, GSK, Merck, Novartis, Roche and Eli Lilly have either licensed compounds or have established alliances with biotechnology companies to develop siRNA drugs.


Cefixime tablets Suprax (Lupin) Urinary tract infections US
Sertaconazole nitrate 2% cream Onabet (Glenmark) Fungal infections India
Melatonin Circadin (Lundbeck) Insomnia Germany
Desvenlafaxine Pristiq (Wyeth) Depression US
Nilotinib Tasigna (Novartis) Chromosome-positive chronic myeloid leukaemia UK

RNAi in the pipelines

Opko Health is developing bevasiranib for the treatment for wet age-related macular degeneration (AMD). Bevasiranib is an siRNA therapeutic that silences the gene responsible for the production of VEGF (believed to cause vision loss associated with wet AMD).

In phase II trials, bevasiranib inhibited the growth of choroidal neovascularisation and Opko have now initiated a pivotal phase III trial that will assess bevasiranib administered intravitreally. This method of administration has the advantage of delivering siRNA directly to the eye. Such local delivery reduces the chance of the drug breaking down before reaching the target and decreases the potential for off target effects.

The ease of local delivery makes wet AMD an attractive target for siRNA therapeutics and two other companies have siRNA based drugs in development for wet AMD as a result. AGN 211745 was originally developed by Sirna Therapeutics and is now in phase II trials with Allergan. AGN 211745 also targets VEGF, while Quark's RTP 801i-14 (REDD14NP), which has been licensed to Pfizer and is in phase I clinical trials, is designed to inhibit the hypoxia-inducible gene, RTP 801.

ALN-RSV01 is another siRNA therapeutic designed for local delivery, but in this case, it is administered to the lungs using an aerosol. ALN-RS01 is in development with Alnylam Pharmaceuticals for the treatment of infections due to the respiratory syncytial virus (RSV). RSV infections can lead to serious respiratory conditions such as croup, pneumonia and bronchiolitis. Morbidity and mortality from RSV infections is particularly significant in patients who have compromised cardiac, pulmonary or immune systems, such as premature infants and lung transplant patients.

ALN-RSV01 works by silencing the nucleocapsid N gene, which is critical for viral replication. Positive results from proof of concept studies of ALN-RSV01 in adult patients infected with RSV have been reported by Alnylam. In a phase II trial, intranasal delivery of ALN-RSV01 was efficacious in decreasing the infection rate and increasing the number of infection-free subjects. Alnylam believes that this is a significant step forward in the development of siRNA based drugs.

In April 2008, Alnylam went on to initiate a phase II trial of ALN-RSV01 in adult lung transplant patients naturally infected with RSV. In the previous trial, healthy subjects were inoculated with the virus. The transplant patients will be administered ALN-RSV01 via inhalation using a nebuliser, which is the delivery option that the company intends to commercialise. The company also expects to initiate trials in paediatric patients later this year.

Other siRNA therapeutics in clinical development include Quark's AKLi5 (15NP) and TransDerm's TD101. AKLi5 was developed, like Quark's other clinical candidate, RTP 801i-14, in conjunction with Silence Therapeutics.

AKLi5 targets the p53 gene, a transcription factor that activates apoptosis and other cellular pathways in response to stress. AKLi5 is being investigated for the prevention of acute kidney injury in patients undergoing cardiovascular surgery. Temporary inhibition of p53 at the time of injury may delay the induction of cell death, thereby allowing natural repair mechanisms to restore normal function. Administration of a single intravenous injection of AKLi5 is being evaluated in phase I clinical trials. TD101 is in phase Ib development for the treatment of the rare skin disorder, pachyonchyia congenita (caused by a mutation in several genes that encode for keratin). Initial trials will investigate a transdermal injection, but the company plans to develop a topical cream formulation.

There are still a number of hurdles to overcome before therapeutics based on RNAi can realise their full potential. First, siRNA molecules usually need to be chemically stabilised before they can function as useful therapeutics. Then the molecules must be effectively delivered into cells and maintain therapeutic levels over a period of time. While local administration of 'naked' siRNA has proved effective, for systemic administration the siRNA must be modified or formulated in order to reach the desired tissue.

Methods under investigation include encapsulating siRNA molecules in liposomes, or conjugating siRNA to lipids or other targeting molecules such as antibodies and chemical ligands. In addition, it is essential that exogenously produced siRNA will not activate the body's immune system, interfere with the body's own miRNA or cause intolerable toxicity.

The challenges are still great and no therapeutic based on interfering RNA has yet reached the world market. It seems likely, however, that in the near future these molecules will contribute significantly to the fight against human diseases.

The Author
Victoria Muir
- Managing Editor, R&D Insight

4th June 2008


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