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A novel strategy for stimulating theproduction of utrophin, a proteinfound in muscle, has shown promisingresults as a possible therapy forDuchenne muscular dystrophy(DMD). However, lead author TejvirKhurana (University of PennsylvaniaSchool of Medicine, Philadelphia, PA,USA) cautions that the work is stillpreliminary, and believes that it needsfurther preclinical development beforeproceeding to human trials.

DMD is a progressive andinvariably fatal disease, with symptomsbeginning in early childhood. It iscaused by a genetic mutation thatresults in the absence of the proteindystrophin, which is needed for musclefunction. The direct way of trying tocorrect the problem is to replacedystrophin by gene therapy. Previousresearch in mice suggests that utrophin,which is closely related to dystrophin,may be able to take over the function ofdystrophin. So, says Khurana, “we’ve

gone about it slightly differently, andinstead used what we call functionalsubstitution. Our strategy was toincrease the expression of a pre-existingrelated gene, rather then deliver themissing gene by gene therapy.”

Khurana and co-workers attemptedto boost existing concentrations ofutrophin, thus bypassing the need toreplace dystrophin. They gaveintraperitoneal injections of a smallpeptide fragment called heregulin tomale mdx mice, which are deficient indystrophin, to stimulate production ofutrophin. After 3 months, utrophinconcentrations had tripled and therewas improvement in the quality andphysiological properties of the muscletissue. Although the mice were notcured, the overall pathology wasimproved (Proc Natl Acad Sci USA2004; 101: 13856–60).

There is no reason why thisapproach shouldn’t work in humanbeings, says Khurana, but we would

first want to do a long-term study inmice as well as in other animal modelsto see what the effects are over a longerperiod of time. “By doing a series oflong-term studies, we will also know ifthis therapy is useful in reversing thedisease, or only useful in stopping itsprogression”, he explains.

The success of future therapies forDMD will depend on the developmentof safe procedures that do not triggerimmunological reactions and avoidcytotoxic side-effects, points out KayOhlendieck (National University ofIreland, Maynooth, Ireland). “Manybiomedical researchers in the fieldbelieve that introduction of dystrophininto an organism, that has never seenthis molecule due to a geneticdeficiency, might trigger anautoimmune response in the long-term. Thus, utrophin upregulation isan excellent alternative in avoiding thispotential complication.”Roxanne Nelson

Utrophin therapy for Duchenne muscular dystrophy?

Neurology Vol 3 November 2004 http://neurology.thelancet.com

Syncytin, a protein encoded by ahuman endogenous retrovirus (HERV)envelop gene, is associated with redox-related death of oligodendrocytes anddemyelination in lesions in the brains ofpatients with multiple sclerosis (MS).

HERVs are sections of the humangenome that originated as retroviralDNA transcripts and became integratedinto human chromosomes. ChrisPower (University of Calgary, Canada),lead author of the paper explained that,although most of the 20 or so differentfamilies of HERVs scattered around thehuman genome are quiescent, severalHERVs have been implicated inphysiological processes and disease.

Power and colleagues in Canada,France, the UK, and the USA examinedthe abundance of different HERVmRNAs in the brains of patients withMS. After finding an abundance ofHERV-W env mRNA, the researchersused western blotting to look forsyncytin, the protein encoded by thisgene. Patients with MS had three timesthe amount of syncytin found in thebrains of healthy people (Nat Neurosci

2004; 7: 1088–95). Moreover, syncytinwas selectively expressed in astrocytesand microglia—cells that mediateneuroinflammation.

When the researchers investigatedthe effects of syncytin in human fetalastrocytes, they found release of reactiveoxygen species and subsequent upregu-lation of proinflammatory molecules inglia. Power and colleagues also foundthat soluble factors released byastrocytes in response to syncytin led tooligodendrocyte damage death. “We arethe first group to show that an HERVenvelope protein has the ability to bepathogenetic”, says Power.

“HERV-W is no longer just a virusyou can find expressed in patients withMS without any knowledge of itssignificance”, says Anné Møller-Larsen(Institute of Medical Microbiology andImmunology, University of Aarhus,Denmark). “Now it has been shownthat it can be at least part of the cause ofthe pathological findings in patientswith MS.” Power, however, does notthink syncytin is the cause of MS,although “it certainly could be an

important molecule in the diseasecascade”.

After the finding of oxidativedamage in glial cells, Power andcolleagues investigated the effects ofantioxidants in human fetal astrocytesand the brains of mice transfected withsyncytin. In both models, theantioxidant ferulic acid decreased theamount of MS-like pathology.

Power says that the findings in thisstudy have important implications forthe understanding of demyelinatingdiseases and indicate potential thera-peutic use of free-radical scavengers,such as ferulic acid. Møller-Larsensuggests that these results might heraldsuccess where previous therapeuticstrategies have failed: “treatment withantioxidants has been tried years agowith selenium as one of the candidates.As other compounds are now primechoices, the antioxidants probablyshowed insufficient effects, but this doesnot exclude the possibility of morepotent antioxidants [being used to treatdemyelinating disorders]”.Peter Hayward

Active HERV protein implicated in demyelination