Brain-Derived Neurotrophic Factor-Mediated Protection of Striatal Neurons in an Excitotoxic Rat Model of Huntington's Disease, as Demonstrated by Adenoviral Gene Transfer

Abstract

Huntington's disease (HD) is a genetic disorder leading to the degeneration of striatal GABA-ergic output neurons. No treatment is currently available for this devastating disorder, although several neurotrophic factors, including brain-derived neurotrophic factor (BDNF), have been shown to be beneficial for striatal neuron survival. We analyzed the effect of adenovirus-mediated transfer of the BDNF gene in a model of HD. Using a stereological procedure, three groups of rats were given an intrastriatal injection of adenovirus encoding BDNF, beta-galactosidase, or sham surgery. Two weeks after treatment, the animals were lesioned with quinolinic acid (QUIN), a toxin that induces striatal neuron death by an excitotoxic process. One month after the lesion, histological study revealed that striatal neurons were protected only in rats treated with the BDNF adenovirus. Volume measurements showed that the QUIN-induced lesions were 55% smaller in the BDNF adenovirus-treated group than in the beta-galactosidase adenovirus-treated group (p < 0.05), and the sham-treated group (p < 0.05). To determine the survival of striatal GABA-ergic output neurons after the QUIN-induced lesion, we immunostained brain sections with DARPP-32, an antibody specific for striatal output neurons. Prior treatment with the BDNF adenovirus resulted in a cell survival of 64%, whereas that after beta-galactosidase treatment was 46% (p < 0.05), showing that the BDNF adenovirus protected the striatal neurons. These results indicate that transfer of the BDNF gene is of therapeutic value for Huntington's disease.

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

“…This approach alleviates problems associated with existing methods for inhibiting apoptosis, including limited delivery into the cell, repeated or chronic injection/infusion protocols, and lack of specificity to apoptotic pathways. Over the past two years, several studies reported the use of replication-deficient viral-mediated gene transfer to successfully overexpress a number of proteins in the CNS (Choi-Lundberg et al, 1997;Bemelmans et al, 1999;Franklin et al, 1999;Kitagawa et al, 1999;Bohn et al, 2000;Eberhardt et al, 2000;Fathallah-Shaykh et al, 2000;Huber et al, 2000;Kordower et al, 2000;Watabe et al, 2000;Yagi et al, 2000;Yukawa et al, 2000;Boer et al, 2001;Watabe et al, 2001). Recombinant adenovirus gene transfer has also been used to express functional proteins in the spinal cord (Smith et al, 1996;Smith et al, 1997;Romero and Smith, 1998;Smith and Romero, 1999;Romero et al, 2000).…”

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

“…Wt-htt increases the transcription of the brain-derived neurotrophic factor (BDNF) (Zuccato et al 2001), a neuroprotective factor for striatal (Bemelmans et al 1999;Perez-Navarro et al 1999Kells et al 2004) and dopaminergic neurons (Hyman et al 1991). This beneficial activity of wt-htt is lost when the protein is mutated as, under these conditions, BDNF expression is reduced (Ferrer et al 2000;Zuccato et al 2001Zuccato et al , 2003.…”

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

“…First-generation adenoviral vectors are powerful vectors for gene transfer and gene therapy in the CNS (Bilang-Bleuel et al, 1997;Bemelmans et al, 1999;Dewey et al, 1999;Bjorklund et al, 2000;Mittoux et al, 2000;Sandmair et al, 2000;Maleniak et al, 2001;Mittoux et al, 2002;Biglari et al, 2004;Chiocca et al, 2004;Do Thi et al, 2004;Gondi et al, 2004;HurtadoLorenzo et al, 2004;Immonen et al, 2004). As a result, recent trials have shown adenoviral vectors encoding HSV1-TK to be effective in randomized clinical trials for brain glioblastoma multiforme, compared to patients treated with standard treatment.…”

“…Experimentally, they are successful in gene therapy models of many brain diseases, including Parkinson's disease (Bilang-Bleuel et al, 1997;Bjorklund et al, 2000;Do Thi et al, 2004;), Huntington's disease (Bemelmans et al, 1999;Mittoux et al, 2000;Mittoux et al, 2002), brain tumors (Dewey et al, 1999;Sandmair et al, 2000;Maleniak et al, 2001;Biglari et al, 2004;Chiocca et al, 2004;Gondi et al, 2004;Immonen et al, 2004) and various pain syndromes (Cope et al, 2006). In comparative clinical trials of gene therapy for malignant brain tumors, first-generation adenoviral vectors are significantly more effective than retroviral vectors, utilizing the conditional cytotoxic gene HSV 1 -TK and ganciclovir (Immonen et al, 2004).…”