CELLULAR DELIVERY OF HUMAN CNTF PREVENTS MOTOR AND COGNITIVE DYSFUNCTION IN A RODENT MODEL OF HUNTINGTONS-DISEASE

The delivery of ciliary neurotrophic factor (CNTF) to the central nerv ous system has recently been proposed as a potential means of halting or slowing the neural degeneration associated with Huntington's diseas e (HD). The following set of experiments examined, in detail, the abil ity of human CNTF (hCNTF) to prevent the onset of behavioral dysfuncti on in a rodent model of HD. A DHFR-based expression vector containing the hCNTF gene was transfected into a baby hamster kidney fibroblast c ell line (BHK). Using a polymeric device, encapsulated BHK-control cel ls and those secreting hCNTF were transplanted bilaterally into rat la teral ventricles, Eight days later, the same animals received bilatera l injections of quinolinic acid (QA, 225 nmol) into the previously imp lanted striata, A third group received sham surgery (incision only) an d served as a normal control group, Bilateral infusions of QA produced a significant loss of body weight and mortality that was prevented by prior implantation with hCNTF-secreting cells, Moreover, QA produced a marked hyperactivity, an inability to use the forelimbs to retrieve food pellets in a staircase test, increased the latency of the rats to remove adhesive stimuli from their paws, and decreased the number of steps taken in a bracing test that assessed motor rigidity, Finally, t he QA-infused animals were impaired in tests of cognitive function-the Morris water maze spatial learning task, and the delayed nonmatching- to-position operant test of working memory, Prior implantation with hC NTF-secreting cells prevented the onset of all the above deficits such that implanted animals were nondistinguishable from sham-lesioned con trols, At the conclusion of behavioral testing, 19 days following QA, the animals were sacrificed for neurochemical determination of striata l choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GA D) levels, This analysis revealed that QA decreased striatal ChAT leve ls by 35% and striatal GAD levels by 45%, In contrast, hCNTF-treated a nimals did not exhibit any decrease in ChAT levels and only a 10% decr ease in GAD levels, These results support the concepts that implants o f polymer-encapsulated hCNTF-releasing cells can be used to protect st riatal neurons from excitotoxic damage, produce extensive behavioral p rotection as a result of that neuronal sparing, and that this strategy may ultimately prove relevant for the treatment of HD. (C) 1997 Elsev ier Science Inc.