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The US National Multiple SclerosisSociety (NMSS) has awarded thelargest ever research grant for multiplesclerosis (MS) to four research teamsas part of the society’s Promise 2010campaign. The initiative involvesgroups led by researchers in the USAand the UK, with collaborating centresin Canada, France, and Italy.

$15·6 million of an eventual$30 million has been divided amongthe groups working on differentaspects of MS screening, monitoring,myelin repair, and neuronal protectionwith new technologies including cell-based and genome-based approaches.

Ian Duncan is the principalinvestigator of a group based at TheUniversity of Wisconsin (Madison, WI,USA) that will investigate the

potential for cell-based remyelination.“The NMSS have been very bold inawarding grants to projects such asours in which we are investigatingtechnologies that 10 years ago peoplewould not have thought of as beingclinically relevant”, Duncan toldThe Lancet Neurology.

The initiative is not only unusual in itsinvestment in new and controversialtechnologies—the awards to non-USgroups by a national association is aninnovative move. Gavin Giovannoni(Institute of Neurology, London, UK)says that the project will bring togethera team of scientists and clinicians withdifferent skills. “Our work”, Giovannonisays, “is complementary to that of theother groups and we plan to collaboratewith them.” Giovannoni and colleaguesare trying to identify new biomarkersto monitor patients with MS inneuroprotective and neurorestorativeclinical trials and to find neuroprotectivemolecules and combination therapiesthat prevent progression to secondary-progressive MS.

The other UK led group willinvestigate “the potential for therapiesaimed at stem and precursor cellpopulations of the CNS to promoterepair in MS”, explains principalinvestigator Charles ffrench-Constant(Cambridge University, UK). Specif-ically, ffrench-Constant’s collaboratorsbased in France, Italy, Canada, the

USA, and the UK will target neuralstem cells that persist in the brain evenafter MS-associated damage. “From atherapeutic viewpoint, reactivation ofthese cells would be preferable totransplantation based approacheswith their attendant cost and risk.”

The fourth group to win an award isled by Johns Hopkins University(Baltimore, USA) researcher PeterCalabresi. Using rodent models andneuronal cultures, Calabresi andcolleagues will investigate mechanismsof axonal damage in MS.

The ultimate aim of the Promise2010 campaign is to develop thesenascent technologies into potentialtherapies for clinical trial within thenext 5 years. With some of thegroups working at very basic levels,this is an ambitious goal. Althougheach group is focusing on distinctnew areas of research “theseoverlapping but distinct researchthemes should maximise output”,ffrench-Constant told The LancetNeurology.

Duncan hopes that although thegroups were competitors for grants,now the funds have been awarded theresearchers will be able to pulltogether in their attempts to developtherapies for trial by the end of thecampaign.

Peter Hayward

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Largest ever funding for multiple sclerosis research projects

Evidence is mounting on the role ofderegulated brain microcirculation intriggering Alzheimer’s disease (AD).A pathogenic cascade that begins witha compromised neurovascular unitcould either provoke brain injury orexacerbate any previous damage. In anew study, Berislav Zlokovic(University of Rochester, NY, USA) andcolleagues show that the proteinMEOX2, a homeobox transcriptionfactor, could be the master gene

controlling a cerebrovascular-diseasepathway in AD. The researchers reporthow changes in the concentration ofMEOX2 can control brain angiogenesis,clearance of amyloid-� peptide (A�),and cerebral blood flow (Nature Med2005; published online Aug 14,DOI:10.1038/nm1287).

According to Jack DeLaTorre(Case Western Reserve University,Cleveland, OH, USA), a long-timeadvocate of the neurovascular

hypothesis of AD, “Zlokovic’s findingsadd another notch of support to ourconcept of cerebral hypoperfusion asthe cause of AD”.

By comparing the transcriptomeprofile (over 12 000 genes) of neuro-vascular cells from the cortex ofhealthy individuals to that of patientswith AD, the researchers found thatMEOX2 concentrations were reducedin patients with AD. To understandMEOX2 participation in the cause of

More support for vascular basis of Alzheimer’s disease

Researchers will investigate strategies to promote remyelination

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the disease, they used an in vitromodel of brain endothelial cells (BECs).Silencing of MEOX2 in otherwisehealthy BECs reduced their survivalrate and impaired the formationof capillary tubes. Moreover, sup-pression of MEOX2 reduced thehalf-life of LRP, the A� clearancereceptor at the blood–brain barrier.Conversely, restoration of MEOX2expression in BECs from patients withAD produced a clear angiogenic effectand inhibited apoptosis.

Analysis of mice in which MEOX2 waspartially deleted (MEOX2+/-) providedfurther support for this gene‘sinvolvement in brain vascular function.The investigators detected a largedecrease in cortical cerebral blood flowin these mice, together with altered

capillary angiogenesis. In addition, asthe mice aged they lost the expressionof LRP and accumulated twice as muchA� as their wild-type littermates. Theauthors think that these events echoneurovascular pathology in AD: “Lowlevels of MEOX2 and accumulation ofA� may act in concert to inhibitangiogenesis in AD.” MEOX2, mightthen be a promising novel therapeutictarget for neurovascular disorder inAD. DeLaTorre speculates: “Increasingcerebral blood flow by any meanspossible, including restoring MEOX2 inpotential patients with AD, mightprevent or slow down the cognitivemeltdown patients with AD aredoomed to have.”

David Gorski (Robert WoodJohnson Medical School, NJ, USA),

who cloned MEOX2 and has sincecharacterised its function in vasculardifferentiation, told The LancetNeurology: “We consider it likely thatabnormalities in MEOX2 expressionplay a role in diseases in whichangiogenesis is abnormal.” However,he added, “This study does notrule out that decreased MEOX2expression observed in cells isolatedfrom patients with AD maybe secondary to other physiologicalderangements resulting in thepathogenesis of their disease. Theexact relation between derange-ments in MEOX2 and diseases suchas AD, atherosclerosis, and cancerremains to be elucidated.”

Elena Becker-Barroso

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Nasal vaccination has been shownto reduce the amyloid-� peptide(A�) burden in mouse models ofAlzheimer’s disease (AD). Althoughinitial studies of immunisation inhuman beings with AD were stoppedbecause some people developedmeningoencephalitis, this new form ofimmune therapy could be welltolerated by human beings.

Previous research has shown thatA� has an important role in thepathogenesis of AD and thatimmunisation with anti-A� anti-bodies can clear amyloid depositsin vitro and in mice. Howard Weiner(Harvard Medical School, Boston, MA,USA) and colleagues tested avaccination of glatiramer acetate anda proteosome-based adjuvant usingnasal administration in a mouse modelof AD (J Clin Invest 2005; publishedonline Aug 11, DOI:10.1172/JCI23241). The mucosal adjuvant hasalready been used safely in humanbeings, and glatiramer acetate, whichis approved by the US Food and DrugAdministration, has been usedsubcutaneously to treat patients withmultiple sclerosis.

The researchers found significantlylower amounts of A� in mice giventhe nasal vaccination than in controls.Their findings suggested that thetreatment activated microglia, whichcolocalised with A� fibrils in the brainwithout producing toxic effects.Microglial activation after sub-cutaneous vaccination and nasalvaccination also correlated withincreased numbers of T cells. Thus, theresearchers postulate that these T cellsparticipate in promoting microglialactivation.

Although an inflammatory com-ponent in AD is now well accepted, “ithas been a matter of discussionwhether targeting the inflammation inthe AD brain would be beneficialor detrimental”, says MarianneSchultzberg (Karolinska Institute,Stockholm, Sweden). “This study willfuel research into further investigationof how to stimulate the beneficialcomponent of brain inflammation andto prevent potential side-effects.”

“Our results will provide a new focusin trying to activate microglia ratherthan inducing anti-A� antibodies”,says Weiner. “However, not all

approaches that work in animals willwork in human beings. Thus, humantrials are crucial.”

Christopher Janus (Mayo ClinicJacksonville, FL, USA) agrees that “thestudy adds new perspective toimmunotherapy in AD with a strongpotential for further testing”, butstresses extreme caution before anytherapeutic recommendations aremade, because of the adverseside-effects seen in previous clinicalstudies.

Vivien Chen

Novel method of treating Alzheimer’s disease

Could nasal administration of an AD vaccine be a possibility?

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