RNA and RNAi

Alnylam Pharmaceuticals, Inc. announced that it has published data in the journal Oligonucleotides demonstrating robust silencing of an endogenous oligodendrocyte gene with small interfering RNAs (siRNAs), the molecules that mediate RNAi, when administered by direct delivery to the central nervous system (CNS) in both rats and non-human primates.

"These data extend the successful delivery of siRNAs in vivo to an important additional cell type within the CNS," said Dinah Sah, Ph.D., Vice President, Research, CNS, and Oncology of Alnylam. "While previous studies have shown successful CNS delivery of siRNAs in neurons, this published study shows robust RNAi silencing of oligodendrocyte-specific genes. These findings suggest potential therapeutic applications for RNAi therapeutics in certain diseases demonstrating oligodendrocyte pathology such as progressive multifocal leukoencephalopathy (PML), multiple sclerosis, and cerebral palsy."

"This paper is a yet another proof point of our continued commitment to scientific excellence and also another example of Alnylam's scientific leadership in the RNAi therapeutics field," said Jack Schmidt, M.D., Chief Scientific Officer of Alnylam. "Indeed, this is the fourteenth paper Alnylam has published in 2008, well exceeding our goal of ten or more scientific papers published in peer-reviewed journals this year."

The research (Querbes et al. Oligonucleotides 18 December 2008; DOI: 10.1089/oli.2008.0165) conducted by Alnylam scientists, some of which was presented at the Keystone RNAi meeting earlier this year, demonstrated that in vivo silencing of an endogenous oligodendrocyte-specific gene by an RNAi therapeutic was dose dependent, durable, and mediated by an RNAi mechanism. Specifically, the data showed that:

-- siRNAs administered in a rodent model achieved successful delivery and silencing of an endogenous oligodendrocyte gene target (2′,3′-cyclic nucleotide 3′-phosphodiesterase or "CNPase") in a specific manner as compared with a control siRNA;

-- direct CNS delivery of siRNA in the rodent model silenced the CNPase mRNA by approximately 75 percent, as compared with a control siRNA, and was durable for up to one week;

-- increasing the infusion rate increased the distribution of CNPase mRNA suppression in white matter regions distant from the infusion site;

-- CNPase silencing was mediated by an RNAi mechanism as measured by 5'RACE; and,

-- direct infusion of an siRNA into the CNS in a non-human primate model resulted in silencing of the CNPase mRNA by 55 percent.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. RNAi therapeutics target the cause of diseases by potently silencing specific messenger RNAs (mRNAs), thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

Source: Medical News Today © 2009 MediLexicon International Ltd (05/01/09)

A Dr Hadwen Trust-funded pilot study at Imperial College, London, is investigating whether the application of a new molecular technique could replace animal experiments in Multiple Sclerosis (MS) research. MS is a debilitating disease of the nervous system, affecting around 2.5 million people worldwide and with currently no cure. Animal experiments on guinea pigs, rabbits, monkeys and rodents have been of dubious value, artificially creating a condition that differs markedly from true MS.

Decades of animal experiments for MS have involved artificially inducing a condition called Experimental Autoimmune Encephalomyelitis (EAE) in animals in the hope of creating a ‘model’ of human MS. The animals suffer inflammation and damage to the nervous system resulting in paralysis, and in more recent examples EAE has also been studied in genetically modified mice, either ‘humanised’ by adding human genes or with genes ‘knocked out’.

These experiments not only cause animal suffering, but are also of questionable relevance to MS patients. The differences between human MS and EAE are significant, and despite more than 10,000 published experiments on animals with EAE, the human disease remains poorly understood, treatments are very limited and a cure remains elusive. Even worse, some neurology experts fear that reliance on the animal model has delayed MS research by years. For the sake of animals and people, more advanced non-animal approaches to studying MS are urgently needed.

The Dr Hadwen Trust is funding Professor Daniel Altmann to conduct a unique one year pilot study looking at a functional analysis of the T cell immune response in multiple sclerosis by gene silencing. Hallmark damage to the nervous system seen in MS is believed to be caused by the patient’s own immune system attacking and damaging the nerves. Patients’ immune cells can be obtained from blood samples and studied in culture. In this new project at Imperial College, a new molecular technique called RNA knockdown will be applied to immune cells from MS patients. Particular genes in the immune cells will be turned-off to see which ones are contributing to the immune responses that underlie MS. This is a completely new approach to MS research and if successful, it could replace experiments on genetically modified ‘knockout’ mice with induced EAE, who are currently used to investigate the contribution of immune system genes to MS.

Says Nicky Gordon, Dr Hadwen Trust:
“It’s clear that current so-called animal models for MS are not delivering the research results that we so desperately need to tackle this devastating disease. Animals don’t naturally suffer from MS, and the condition they are artificially made to suffer in the laboratory differs so significantly from real MS, it is little wonder that progress has been slow. There is an urgent need for scientists to revise their faith in the traditional animal techniques, and look instead to new possibilities opened up by non-animal methods. That’s why the Dr Hadwen Trust is funding this pilot study at Imperial College. It’s using a totally new technique that has never been applied to MS research before, but it shows real promise and we are confident that only by championing the very latest and experimental non-animal research, will we find the best ways to treat and cure diseases like MS.”

The Dr Hadwen Trust’s latest research project has been warmly welcomed by supporter, Fay Emerson, who has Multiple Sclerosis.
“I suffer from Multiple Sclerosis,” says Fay, “and I do not wish experiments to be carried out on animals ‘in my name’. This is because I believe research into my illness has been held back many years by this outdated and unreliable method. I support the non-animal methods which are promoted by the Dr Hadwen Trust which are more truly scientific than experimenting on a species which is very different from ours. It is not only more reliable to use other non-animal tests but also more humane. If more people knew the truth about the unreliability of animal experiments and the danger such methods put the human population in, they would not condone or allow them to continue.”

Source: Dr Hadwen Trust © Dr Hadwen Trust 2007 (04/09/07)