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severely impair autobiographical recall.In addition, images evoked duringautobiographical recall are usuallyviewed from the first-personperspective. Squire and co-workersfound that subjective experiences ofrecollection were normal in the fivepatients with damage restricted mainlyto the medial temporal lobe.

These findings show that “whenthere is loss of remote memory forevents that are specific to time andplace as a result of brain damage, somedamage must have occurred outsidethe medial temporal lobe”, first authorPeter Bayley told The Lancet Neurology.More specifically, “when there is a loss

of remote autobiographical memory forspecific events, patients have damageto the neocortex, including the frontal,lateral temporal, or occipital regions”.

Squire’s team has taken a critical stepto “shed new light on the relationshipbetween the extent of damage andmemory loss”, says Paul Frankland(Hospital for Sick Children ResearchInstitute, Toronto, Canada). “Theyshow that when damage is limitedto the medial temporal lobe, retro-grade amnesia is graded, with morepronounced loss of recent memories.However, when damage also includesadditional damages to the neocortex,both old and new memories are lost.”

These results are consistent withdata from imaging studies in mice,which have shown that when mice arereminded of a recent memory, thehippocampus is activated. However,when they are reminded of anolder event, a number of differentneocortical sites are activated,suggesting that memories undergo aprolonged process of reorganisationafter initial encoding. Squire’s groupplans to build on current research byusing functional brain imaging tostudy healthy human volunteers andmemory-impaired patients.

Laura Thomas

http://neurology.thelancet.com Vol 4 August 2005 461

Peripheral neuropathic pain iscommon but difficult to treat. Genetherapy could be the way forward.David Fink and colleagues at theDepartment of Neurology, Universityof Michigan Health System (Ann Arbor,MI, USA) and the University ofPittsburgh (PA, USA) transferred theglutamic acid decarboxylase (GAD)gene into the dorsal-root ganglion ofrats by use of a herpes-simplex virus-based vector injected under the skin.The result was a significant effect onpain responses. “GABAergic therapyfor neuropathic pain has had limitedsuccess but gene transfer achievesrelease of the neurotransmitter in thedorsal horn”, comments Fink.

The group previously used the samevector system to transfer proenkephalinand glial cell-derived neurotrophicfactor, but the size of the anti-touchsensitivity effect achieved with theGAD67-expressing vector was muchgreater. “This finding could reflect therole of reduced spinal GABAergic tonein the pathogenesis of neuropathic painand the selective ability of this vector tocorrect it locally”, adds Fink.

“This study is certainly very pro-vocative in that HSV-GAD treatmentclearly attenuates accepted measuresof neuropathic pain”, comments

Raymond Chavez (Avigen, Alameda,CA, USA). Chavez and colleagues KirkJohnson (Avigen) and Linda Watkins(University of Colorado, Boulder, CL,USA) are looking at the role of glialactivation in neuropathic pain states.“Our work with IL-10 has shown a veryclear link between proinflammatorycytokine activity and neuropathicpain”, explains Johnson. “We havedemonstrated that non-viral genetherapy techniques that drive the localexpression of heterologous IL-10 canproduce a long-term (ie, 2–3 month)reversal of touch sensitivity by inhibit-ing the release and activity of pro-inflammatory cytokines in the spinalcord.” GABAergic activation can lead tothe suppression of cytokine releasefrom microglia, suggesting a commonpathway by which IL-10 and GAD over-expression could function, he says.

“I most definitely see gene therapytreating chronic pain in the next fewyears”, enthuses Watkins, but sheagrees that some issues still need to beresolved. The first issue is theidentification of suitable targets, whichnecessitates a much more thoroughunderstanding of glial cell biology,explains Chavez. It will also be vital toextend our knowledge of themechanisms and suitability of various

gene-therapy approaches in anatomicalregions critical to the pain pathway,such as the spinal cord and thethalamus, he adds.

Johnson notes that more informationand experimental testing of regulatorymechanisms will be needed to reassurepatients that the expression ofheterologous genetic material will betransitory and carefully controlled. “Butall of this work appears achievableon a relatively short time horizon”,concludes Watkins.

Kathryn Senior

Can gene therapy take the pain away?

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Dorsal root ganglia could be potential targets for gene therapy for neuropathic pain

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