Cellular Delivery of Human Cntf Prevents Motor and Cognitive Dysfunction in a Rodent Model of Huntington's Disease

Abstract

The delivery of ciliary neurotrophic factor (CNTF) to the central nervous system has recently been proposed as a potential means of halting or slowing the neural degeneration associated with Huntington's disease (HD). The following set of experiments examined, in detail, the ability of human CNTF (hCNTF) to prevent the onset of behavioral dysfunction in a rodent model of HD. A DHFR-based expression vector containing the hCNTF gene was transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting hCNTF were transplanted bilaterally into rat lateral ventricles. Eight days later, the same animals received bilateral injections of quinolinic acid (QA, 225 nmol) into the previously implanted striata. A third group received sham surgery (incision only) and 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, the 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 hCNTF-secreting cells prevented the onset of all the above deficits such that implanted animals were nondistinguishable from sham-lesioned controls. At the conclusion of behavioral testing, 19 days following QA, the animals were sacrificed for neurochemical determination of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) levels. This analysis revealed that QA decreased striatal ChAT levels by 35% and striatal GAD levels by 45%. In contrast, hCNTF-treated animals did not exhibit any decrease in ChAT levels and only a 10% decrease in GAD levels. These results support the concepts that implants of polymer-encapsulated hCNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage, produce extensive behavioral protection as a result of that neuronal sparing, and that this strategy may ultimately prove relevant for the treatment of HD.

Molecular Targets and Therapeutic Strategies in Huntingtons Disease

“…The delivery of CNTF by Moreover, work with cultured mouse astrocytes suggests that riluzole upregulates the expression of different encapsulated genetically modified cells in HD has later been addressed. Encouraging results were obtained with BHK cells secreting the human CNTF, when implanted in the striata of rodent and non-human primate, in acute and semichronic toxic models of HD [265,[321][322][323]. The preclinical studies led to a clinical trial using this approach which ended recently [324,325].…”

Established and Emerging Therapies for Huntingtons Disease

“…These cells have the additional capacity to be genetically modified to express certain growth factors which may slow the disease down. This disease modifying effect is typically investigated experimentally using excitotoxic mouse and non human primates as a model of HD [123,124]. This has now been investigated clinically using cilary neurotrophic factor, in which cells engineered to deliver this growth factor have been placed in the ventricles of patients with HD, as a cell implant within a semipermeable polymer capsule.…”

Cellular Therapies for Huntington’s Disease

“…Where a limited amount of a protein is required for relatively short periods of time, polymer microspheres are an attractive alternative as they are biodegradable and subsequent surgical procedures are not required for retrieval (Date et al, 2001). However, improvements in the duration of release have been obtained by the use of encapsulated cells engineered to produce the desired molecules (Emerich, 1999, Emerich et al, 1997. Here, cells engineered to secrete specific substances such as neurotrophic factors are protected from the host immune system by a semi-permeable selective biocompatible outer membrane (Emerich, 1999, Emerich, 2004, Emerich et al, 1998, Emerich et al, 1997, Emerich et al, 1996.…”

“…However, improvements in the duration of release have been obtained by the use of encapsulated cells engineered to produce the desired molecules (Emerich, 1999, Emerich et al, 1997. Here, cells engineered to secrete specific substances such as neurotrophic factors are protected from the host immune system by a semi-permeable selective biocompatible outer membrane (Emerich, 1999, Emerich, 2004, Emerich et al, 1998, Emerich et al, 1997, Emerich et al, 1996. The outer membrane allows the entry of nutrients to the cells whilst also allowing the exit of neuroactive molecules.…”