June 27, 2012

expert reaction to study of gene therapy for nicotine addiction

A mouse study raised the potential of a gene therapy treatment for nicotine addiction via an anti-nicotine antibody which prevents nicotine from entering the brain, according to a study in Science Translational Medicine.

Stephanie Sumner-Jones, postdoctoral researcher, UK Cystic Fibrosis Gene Therapy Consortium, University of Oxford, said:

“Ron Crystal’s team have built on the experience of others in developing a vaccine-based strategy to kerb the addictive effects of nicotine: instead of attempting to get a nicotine-specific response by exposure to an immunogenic complex, they are using a small non-pathogenic virus to produce anti-nicotine antibody from the liver, and have achieved higher titres than three other vaccines. The antibody levels were sufficient to decrease the amount of nicotine reaching the brain by 85% compared to controls, and importantly, to prevent the effect of exposure to nicotine in physiological and behavioural assays. If further studies in other models confirm the data presented by Crystal’s team, this has the potential to provide a novel and effective strategy for quitting smoking.”

Darren Griffin, Professor of Genetics at the University of Kent, said:

“The work is of course both impressive and intriguing with great potential. Nicotine addiction is, indirectly, one of the biggest killers in the world. The main issue in terms of going forward to humans is whether the observed biochemical effects in lab mice genuinely translate to a reduced addiction in humans given that such addictions can be both physical and psychological. Issues of safety in humans also need to be addressed.”

Dominic Wells, Professor in Translational Medicine, Royal Veterinary College, London, said:

“The results of this mouse study using gene transfer to produce an anti-Nicotine antibody are very interesting. These types of gene vectors are showing real promise in clinical trials for diseases such as haemophilia. However the experience from haemophilia has taught us that very impressive results in mice generally translate to much less efficient outcomes in man.”

Dr Simon Waddington, Reader in Gene Transfer Technology, University College London, said:

“Over the past decade, gene therapy has shown some promise in treating several devastating diseases including inherited diseases such as haemophilia, severe combined immune deficiency, a type of blindness and cancers such as melanoma and leukemia. The technology underpinning gene therapy is improving all the time and it is encouraging to see these preliminary results that indicate it could be used to address nicotine addiction, which is damaging to the nation’s health and a drain on the health service economy.

“This research group has a long track record in studying how gene therapy might be used to tackle brain diseases ranging from childhood-onset neurodegenerative diseases to cocaine addiction.”

Robert MacLaren, Professor of Ophthalmology, University of Oxford, said:

“The use of gene therapy to treat what is essentially a non-genetic psychological problem is a concept that would have been unthinkable ten years ago. Whilst there may be easier ways of quitting smoking, it could be an exciting concept for other types of drug addiction.”

Professor Anthony Dayan, retired toxicologist (ex-Director of the DHSS Toxicology Department at St Bartholomew’s Hospital, London), said:

“The paper shows interesting results but major questions remain about the activities claimed and their potential as an antismoking therapy.

“There is no doubt that the distribution and persistence of nicotine in the vaccinated mice has greatly changed but all the evidence of a reduction in the actions of injected nicotine depend on acute effects on peripherally distributed nicotine receptors.

“Although the entry of injected nicotine into the brain was reduced no experiment has been done to show whether that reduction is associated with the desired change in addictive effect of nicotine. The report states that “Only 15%” of nicotine entered the brain but would that actually suffice to reduce smoking if it occurred in man?

“In addition, the reduction in the entry of nicotine into the whole brain was only demonstrated very acutely, i.e. 2 minutes after intravenous injection of labelled nicotine. Would the expressed antibody have sufficiently tight binding [affinity] for nicotine to sustain the reduction over a longer period by not slowly releasing antibody-bound nicotine?

“It is implied that the treated animals remained healthy despite the exposure of mice bearing an antibody to the antigen with which it reacts, i.e. they did not experience the sometimes catastrophic effects of an antigen-antibody reaction. An AAV-construct would need to be made that would only lead to generation of a non-harmful type of antibody in man.

“The nature, cost and duration of the development of such a vaccine for humans would require several years of very expensive development. The reader should be made aware that, even if the vaccine were successful, it could not become available to the general public for many years.

“One fundamental question is whether it is ethical to vaccinate someone to produce a potentially life-long immune response against a behavioural pattern, i.e. is making someone persistently produce an immune response against a very common environmental pollutant justifiable? Nicotine addiction via smoking is harmful but is it ethical to produce a major and enduring change in someone’s body to prevent it when other less major types of treatment are feasible?

“There is no generally available human gene therapy yet because the efficacy and safety of this approach to treatment has not yet been proven in humans. A great deal of time and effort will be necessary to demonstrate these points in immediately life-threatening diseases before resources can be directed to this form of behavioural modification for addiction to nicotine.

“The clinical testing of this gene therapy would also be extremely difficult, lengthy and costly because of the need to show safety and retained efficacy in man over a very long period, certainly many months or more likely several years. Who could support such trials other than government agencies and is it politically and financially conceivable they would attack so directly the popular habit of smoking?

“In essence this is a very early announcement of interesting science but it is a very long way from any form or practical therapy. Utilisation of gene therapy to produce behavioural modification raises vast questions, not just of practicality and timing, but also of ethics.”

‘AAV-Directed Persistent Expression of an Anti-Nicotine Antibody Gene for Smoking Cessation’ by Hicks, M. et al., published in Science Translational Medicine on Wednesday 27th June.