Adenoviral Astrocyte-Specific Expression of BDNF in the Striata of Mice Transgenic for Huntington’s Disease Delays the Onset of the Motor Phenotype

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. The most characteristic structural feature of this disease is neurodegeneration accompanied by gliosis in the striatum. BDNF has been proposed to protect striatal neurons from degeneration, because it is an important survival factor for these neurons from development to adulthood. Considering the extensive gliosis and the survival effects of BDNF, we constructed an adenovirus to express a BDNF cDNA in astrocyte cells using a promoter of the glial fibrillary acidic protein gene. Cells stably transfected in vitro with a BDNF cDNA driven by this promoter expressed BDNF and responded to external stimuli increasing BDNF production. When the vector was applied into the striata of mice transgenic for HD, long-term expression of the transgene was observed, associated with a delay of onset of the motor phenotype of the R6/2 HD transgenic mice. The present data indicate that the striatal expression of BDNF is a potential adjuvant for the treatment of HD.

Astrocytes in Neurodegenerative Disease: Table 1.

“…For example, astrocytic mitochondrial dysfunction has been implicated in HD (Oliveira 2010;Schon and Przedborski 2011). In addition, HD astrocytes may be compromised in their ability to release trophic factors, as htt-expressing astrocytes express less brain-derived neurotrophic factor (BDNF) than WT astrocytes (Wang et al 2012), and increasing BDNF production by astrocytes delays the onset of the motor phenotype in transgenic HD mice (Arregui et al 2011). Mutant huntingtin has also been shown to hinder the suppression of production and secretion of the chemokine Ccl5/RANTES, which is another major trophic function of astrocytes (Chou et al 2008).…”

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

“…In addition, unique pathogenesis of each NDD requires a tailored vehicle system designed to deliver a gene of interest to a certain cell type for a given disease. Though genes have been injected or infused directly in the brain (Do Thi et al, 2004; Yang et al, 2013; Mastorakos et al, 2015), obtaining global gene expression has been difficult -(Lisovoski et al, 1997; Arregui et al., 2011). This is attributed to low gene or vehicle diffusion within brain parenchyma (Mastorakos et al, 2015), less viral vector transduction efficiency (Lisovoski et al, 1997), and reduced gene expression driven by weak promoters (Sandhu et al, 2009).…”

“…Therapy-based studies deliver genes to alleviate disease progression based on NDD pathogenesis. For example, low BDNF levels during disease led to testing BDNF gene therapy for HD (Arregui et al, 2011). The same gene and/or delivery system could result in varied outcomes in two studies based on differences in gene delivery route, targeted cell type, and in vitro or in vivo models.…”

“…When AV delivered BDNF to excitotoxic rats (Bemelmans et al, 1999), Quinolinic acid-induced lesion size was reduced and striatal neuron survival increased (Bemelmans et al, 1999). In transgenic HD mice (Arregui et al, 2011), AV-BDNF delivery improved behavior tests and motor phenotype appearance (Arregui et al, 2011). Thus, neurotrophin expression alleviated disease outcomes despite the differences in targeted cell-type, associated disease, and species models reaffirming their applicability as NDD therapeutics.…”

Engineered BDNF producing cells as a potential treatment for neurologic disease

“…With the knowledge that BDNF is neuroprotective, researchers have attempted to increase BDNF production from endogenous cells within the striatum via adenoviral injections [84,85] or through AAV vector injections into the striatum [86] prior to quinolinic acid lesions. Both groups observed an increase in the numbers of cells expressing Dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp32; specific to MSNs) relative to lesioned control animals.…”