Viral vehicle advances ALS therapy

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THE LANCET Neurology Vol 2 October 2003 http://neurology.thelancet.com 589

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Researchers in the USA are hoping fora breakthrough in the treatment ofamyotrophic lateral sclerosis (ALS)after they successfully used a virus totransport insulin-like growth factor 1(IGF-1) genes into diseased motorneurons (Science 2003; 301: 839–42).

In ALS, the motor neurons of thebrainstem and spinal cord graduallydegenerate, leading to atrophy of limb,axial, and respiratory muscles, andeventually to death.

“There is no treatment for ALS”,explains Fred Gage (Salk Institute forBiological Studies, La Jolla, CA, USA),“but this may be because it is hard tocontinuously deliver drugs into theCNS. After our recent discovery that adeno-associated virus [AAV] istransported retrogradely from pre-synaptic terminals back to the nucleiof motor neurons, we decided to testwhether it could deliver genes forneurotrophic factors that mightimprove the course of the disease.”

Gage’s team injected AAVcontaining the IGF-1 gene into therespiratory and limb motor muscles of transgenic mice that overexpresssuperoxide dismutase 1. By use of histochemical techniques, theresearchers showed that the injectedAAV reached viral receptors on localmotor-neuron projections and thentravelled up the axons back to thenuclei, where the IGF-1 gene wasexpressed.

In these mice, disease symptomstypically appear on postnatal day 90,followed by death 30 days later.Injection of AAV carrying the IGF-1gene at postnatal day 60 delayed diseaseonset by 31 days. The treatment alsoincreased median lifespan from123 days to 160 days. Even when diseasesymptoms were already visible, thetreatment significantly improved thecourse of the disease. When injected onday 90, the median lifespan of theanimals was 22 days longer than that of

controls. Furthermore, control animalsshowed substantial muscular disabilityat 100–110 days, whereas similarsymptoms were delayed by 20 days intreated animals. Treated animals alsomaintained their muscular mass andtotal bodyweight for much longer thancontrols.

“IGF-1 appears to be able to bothdelay disease onset and retard itsprogression”, Gage told The LancetNeurology. “Our data suggest this maybe due to the prevention of apoptosis inaffected neurons.”

“The main issue in this devastatingdisease has been getting presumedtherapeutic molecules to the site of thepathology (ie, the motor neuron)”,remarked Douglas Mitchell (RoyalPreston Hospital, Preston, UK). “This isa way of doing it, and it could haveexciting implications for disease-modifying treatments.” Plans for aclinical trial are being drawn up.Adrian Burton

Viral vehicle advances ALS therapy

A newly discovered form of corticallong-term plasticity that occurs afterfever-induced seizures in infantsprovides a possible explanation forthe increase in susceptibility to adult epilepsy that follows thesechildhood seizures.

Ivan Soltesz and colleagues(University of California, Irvine, CA,USA) first found a link between infantfebrile seizures and adult epilepsy in1999, and have now identified a likelyexplanation for the connection. Theresearchers investigated changes in inhibitory GABAergic transmissionin the hippocampus of neonatal rats (postnatal day 10) afterhyperthermia-induced seizures(Neuron 2003; 39: 599–611).

Under normal conditions in the hippocampus, postsynapticallyreleased endocannabinnoids bind toCB1 cannabinnoid receptors onpresynaptic neurons, which causes adecrease in presynaptic GABA releasein a negative feedback manner. Theend result is a decrease in inhibition

of firing in the postsynaptic cell, amechanism termed depolarisation-induced suppression of inhibition(DSI).

“The endocannabinoid-mediatedsystem becomes much more effectiveafter a single episode of prolongedfebrile seizures in infancy”, saysSoltesz. “After the seizures, the sameamount of excitation will lead to aneven larger decrease in inhibition”.DSI after seizures shows a moreprolonged decay compared with DSIin control animals; Soltesz andcolleagues suggest that these effectsoccur as a result of an increase in thenumber of CB1 receptors in asubpopulation of GABA-releasingaxon terminals in the hippocampus.“This is certainly a mechanism thatcould promote hyperexcitabilityand recurrent seizures”, explainsSoltesz. As such, “endocannabinoidscould prove to be extremelypromising, versatile, novel targetsfor future anti-seizure drugdevelopment”, he adds.

The pathophysiological relevanceof this mechanism has, however, yetto be confirmed. “It still remains to bedetermined whether the increasedcannabinoid signalling plays a role inthe lowering of the epileptic thresholdthat follows a febrile seizure”,Giovanni Diana (Istituto Superiore diSanita’, Rome, Italy) told The LancetNeurology.

Stephen Davies (University ofAberdeen, UK) notes: “This paper isnot directly addressing themechanisms of epilepsy. Instead it islooking at the consequences of aseizure event on the activity of theendocannabinoid system . . . and wehave next to no idea what thephysiological role of this systemmight be.” Irrespective of the medicalimplications of this study, Dianathinks that “this paper shouldrepresent the dawn of a series of newstudies on the role of theendocannabinoid system in neuro-logical and psychiatric disease”.Keri Page

Link between infant seizures and adult epilepsy unravelled