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Using an identical canine factor IX expression cassette, they cross-packagedthe genome into virions generated from five AAV serotypes and injectedthem into the muscles of immunodefi-cient mice and FIX knockout mice.Surprisingly, while the time-to-onset ofdetectable serum levels appeared thesame for all serotypes, types 1, 3 and 5produced 100–1000-fold more caninefactor IX than type 2. ‘Simplistically, wethink that this could be because moremuscle cells are capable of taking up thevirus in types 1, 3 and 5,’ says Walsh.This would directly result in increasedprotein leaching into the bloodstream.Furthermore, using green-fluorescent-protein genes in the expression cassette,they found that AAV type 2 could onlyattach to the slow-twitch muscle fibres,

whereas types 1, 3 and 5 also attachedto fast-twitch fibres. The team is now repeating the experiments in haemophil-iac dogs and primates to ensure thereare no key differences in muscle compo-sition between mice and other animals.

Future studiesThe results of these studies will be usedas a benchmark to determine whether aclinical trial is warranted. Studies will beneeded to show that the gene persists inmaking proteins at high levels (so far, results in mice look promising after sixmonths) and that there are no obviousside effects of the introduced virus ormuscle damage when tested in largeranimals.

‘The mice in the experiment were immunosuppressed to avoid the

production of antibodies against thevirus or protein. If we move into clinicaltrials, this will be a major hurdle to overcome,’ says Walsh. If ultimately successful, Walsh believes the deliverysystem could be used for other diseasesthat require an increase in circulatinglevels of a protein. For example, in cancer, he suggests the method couldbe used to produce anti-angiogenesisproteins.

References01 Rabinowitz, J. et al. (1998) Adeno-associated

virus expression system for gene transfer.Curr. Opin. Biotechnol. 9, 470–475

02 Chao, H. et al. (1999) Persistent expression ofcanine factor IX in hemophilia B canines.Gene Ther. 6, 1695–1704

03 Chao, H.J. et al. Several log increase intherapeutic transgene delivery by distinctadeno-associated viral serotype vectors. Mol. Ther. (in press)

Key researchers from both sides of theAtlantic have called for the urgent revi-sion of the regulations of herbal medi-cines. These remarks were made duringa recent seminar in London (UK), spon-sored by the Royal Society of Chemistry(London, UK) and the American ChemicalSociety (Washington, DC, USA).

The dietary supplements market hasbeen one of the fastest growing areas inthe healthcare arena in recent years,particularly in the USA where 50% of thepopulation regularly take supplementsranging from multivitamins for generalwellbeing to alternative herbal remediesfor chronic and serious disease. However,for the majority of these products thereis little, if any, scientific evidence of effi-cacy. This, together with unregulatedadvertising and media coverage, is a po-tential risk to the public who might be

led to believe that herbal remedies are aseffective and safe as conventional medi-cine. Furthermore, the lack of a regu-latory system for these supplementsmeans that the quality and purity of the extract, its toxicity and side effects (e.g. drug–drug interactions, risk topregnancy) and potential for overdosepresent a significant risk to the public.

The need for evidenceEdzard Ernst (Chair in ComplementaryMedicine, Exeter University, UK) pre-sented data from clinical trials that havedemonstrated the efficacy of severalherbal extracts, such as ginkgo biloba,which has been shown to be beneficialin delaying the chemical deterioration of dementia1. Ernst also highlighted the potential problem of drug–druginteractions in patients taking herbal

supplements. For example, it has beenreported that St John’s wort causes in-duction of hepatic P450 enzymes, whichmight reduce plasma levels of concomi-tantly taken medication2. Such interac-tions are of particular concern becausepatients often do not inform their doctorthat they are taking supplements.

Ernst also discussed how negative dataobtained by herbal extract manufac-turers might be withheld, leading to

Flower power: fact or fiction?Joanna Owens, Joanna.Owens@current-trends.com

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inaccurate reports of a supplement’ssafety and efficacy. He emphasized theneed for extensive randomized clinicaltrials, similar to those already publishedfor St John’s wort and ginkgo biloba,which are necessary to distinguish between genuinely beneficial herbalsupplements and those that have littlemedical value and pose significant toxicological risk.

A view from the USAVarro Tyler (Dean and DistinguishedProfessor Emeritis, School of Pharmacy,Purdue University, West Lafayette, IN,USA) discussed how herbal remedies are regulated as dietary supplementsrather than medicines in the USA.Manufacturers of herbal products in theUSA are not allowed to claim that a product has a therapeutic effect.Moreover, they must state that any effect that the product might have hasnot been proven scientifically. The nutri-tional supplement market in the USA is swamped with products that varygreatly in quality, and a recent trend isthe marketing of nutraceuticals, which

are expensive foods containing only asmall amount of herb extract.

Since its initial boom, the supplementsmarket in the USA has been in decline(by 11.9% from 1998–mid-2000), whichis thought to be because of reported sideeffects, drug–drug interactions, variablequality and limited evidence of efficacy.Tyler described how the lack of patentprotection for supplements discouragesclinical studies, and how only a fewproducts have been adequately re-searched; the remainder is based on‘borrowed science’. This leads to aplethora of herbal products that are similar but inferior to well-researchedproducts, which consumers find unsatis-factory, thus causing a decline in sales.Tyler suggested that a potential solutionto this would be to approve herbal reme-dies as over-the-counter or prescriptiondrugs with quality assurance.

Regulating the remediesMichael Baker (Director of Legal andRegulatory Affairs, Proprietary Associationof Great Britain, London, UK) discussedthe existing regulations for herbal

remedies in the UK, and what optionswere available for improving these. Inthe UK, a recent House of Lords report(http://www.parliament.the-stationery-office.co.uk) has outlined recommen-dations concerning the regulation ofherbal remedies, the possibility of settingup centres of excellence for complemen-tary medicine research and the provisionof information sources and training forthe public and healthcare professionals,respectively. With increased funding and research training, combined with effective regulation, herbal remediescould become an invaluable and safe addition to conventional medicine.

AcknowledgementI would like to thank Edzard Ernst for hishelpful comments on this article.

References1 Ernst, E. (1999) Ginkgo biloba for dementia:

a systematic review of double-blind, placebo-controlled trials. Clin. Drug Invest.17, 301–308

2 Ernst, E. (1999) Second thoughts about thesafety of St John’s wort. Lancet 354,2014–2016

Activation of a stress signal transductionpathway – the unfolded protein re-sponse (UPR) – could play an importantrole in nitrogen-sensing in buddingyeast. It could also be a weak point forattack by antifungal agents. MartinSchröder and colleagues at the HowardHughes Medical Institute (Ann Arbor,MI, USA) suggest that the UPR is acti-vated when there is a rich source of ni-trogen and translation rates are high1.The UPR is responsible for transcriptionalinduction of 381 open reading frames in

response to endoplasmic reticulum (ER)stress, including genes for ER-residentchaperones and ER-associated proteindegrading machinery1. The team there-fore proposes that high translation ratescause a build-up of unfolded polypep-tide chains in the ER and UPR activationinduces chaperones that promote pro-tein folding and enable it to catch upwith the supply of unfolded proteins inthe ER. When nitrogen levels drop, trans-lation rates decrease and the UPR isdownregulated.

A protective mechanismDown-regulation of the UPR also stimulates yeast to switch from normal,vegetative growth to either meiosis andasci formation (sporulation) or to fila-mentous pseudohyphal growth (thepathogenic form of many of these or-ganisms)1. By switching to filamentouspseudohyphal growth, yeast can moveand forage for a new nitrogen supply2.‘When the ER is stressed and containsunfolded proteins, the UPR has a protec-tive function, and strains that can activate

A budding role for the UPRSharon Dorrell, Freelance writer