Utrophin therapy for Duchenne muscular dystrophy?
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For personal use. Only reproduce with permission from Elsevier Ltd 637 Newsdesk A novel strategy for stimulating the production of utrophin, a protein found in muscle, has shown promising results as a possible therapy for Duchenne muscular dystrophy (DMD). However, lead author Tejvir Khurana (University of Pennsylvania School of Medicine, Philadelphia, PA, USA) cautions that the work is still preliminary, and believes that it needs further preclinical development before proceeding to human trials. DMD is a progressive and invariably fatal disease, with symptoms beginning in early childhood. It is caused by a genetic mutation that results in the absence of the protein dystrophin, which is needed for muscle function. The direct way of trying to correct the problem is to replace dystrophin by gene therapy. Previous research in mice suggests that utrophin, which is closely related to dystrophin, may be able to take over the function of dystrophin. So, says Khurana, “we’ve gone about it slightly differently, and instead used what we call functional substitution. Our strategy was to increase the expression of a pre-existing related gene, rather then deliver the missing gene by gene therapy.” Khurana and co-workers attempted to boost existing concentrations of utrophin, thus bypassing the need to replace dystrophin. They gave intraperitoneal injections of a small peptide fragment called heregulin to male mdx mice, which are deficient in dystrophin, to stimulate production of utrophin. After 3 months, utrophin concentrations had tripled and there was improvement in the quality and physiological properties of the muscle tissue. Although the mice were not cured, the overall pathology was improved (Proc Natl Acad Sci USA 2004; 101: 13856–60). There is no reason why this approach shouldn’t work in human beings, says Khurana, but we would first want to do a long-term study in mice as well as in other animal models to see what the effects are over a longer period of time. “By doing a series of long-term studies, we will also know if this therapy is useful in reversing the disease, or only useful in stopping its progression”, he explains. The success of future therapies for DMD will depend on the development of safe procedures that do not trigger immunological reactions and avoid cytotoxic side-effects, points out Kay Ohlendieck (National University of Ireland, Maynooth, Ireland). “Many biomedical researchers in the field believe that introduction of dystrophin into an organism, that has never seen this molecule due to a genetic deficiency, might trigger an autoimmune response in the long- term. Thus, utrophin upregulation is an excellent alternative in avoiding this potential complication.” Roxanne Nelson Utrophin therapy for Duchenne muscular dystrophy? Neurology Vol 3 November 2004 http://neurology.thelancet.com Syncytin, a protein encoded by a human endogenous retrovirus (HERV) envelop gene, is associated with redox- related death of oligodendrocytes and demyelination in lesions in the brains of patients with multiple sclerosis (MS). HERVs are sections of the human genome that originated as retroviral DNA transcripts and became integrated into human chromosomes. Chris Power (University of Calgary, Canada), lead author of the paper explained that, although most of the 20 or so different families of HERVs scattered around the human genome are quiescent, several HERVs have been implicated in physiological processes and disease. Power and colleagues in Canada, France, the UK, and the USA examined the abundance of different HERV mRNAs in the brains of patients with MS. After finding an abundance of HERV-W env mRNA, the researchers used western blotting to look for syncytin, the protein encoded by this gene. Patients with MS had three times the amount of syncytin found in the brains of healthy people (Nat Neurosci 2004; 7: 1088–95). Moreover, syncytin was selectively expressed in astrocytes and microglia—cells that mediate neuroinflammation. When the researchers investigated the effects of syncytin in human fetal astrocytes, they found release of reactive oxygen species and subsequent upregu- lation of proinflammatory molecules in glia. Power and colleagues also found that soluble factors released by astrocytes in response to syncytin led to oligodendrocyte damage death. “We are the first group to show that an HERV envelope protein has the ability to be pathogenetic”, says Power. “HERV-W is no longer just a virus you can find expressed in patients with MS without any knowledge of its significance”, says Anné Møller-Larsen (Institute of Medical Microbiology and Immunology, University of Aarhus, Denmark). “Now it has been shown that it can be at least part of the cause of the pathological findings in patients with MS.” Power, however, does not think syncytin is the cause of MS, although “it certainly could be an important molecule in the disease cascade”. After the finding of oxidative damage in glial cells, Power and colleagues investigated the effects of antioxidants in human fetal astrocytes and the brains of mice transfected with syncytin. In both models, the antioxidant ferulic acid decreased the amount of MS-like pathology. Power says that the findings in this study have important implications for the understanding of demyelinating diseases and indicate potential thera- peutic use of free-radical scavengers, such as ferulic acid. Møller-Larsen suggests that these results might herald success where previous therapeutic strategies have failed: “treatment with antioxidants has been tried years ago with selenium as one of the candidates. As other compounds are now prime choices, the antioxidants probably showed insufficient effects, but this does not exclude the possibility of more potent antioxidants [being used to treat demyelinating disorders]”. Peter Hayward Active HERV protein implicated in demyelination
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Transcript of Utrophin therapy for Duchenne muscular dystrophy?
For personal use. Only reproduce with permission from Elsevier Ltd
637
Newsdesk
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
