Gene Ther. 2016 Mar;23(3):283-95. doi: 10.1038/gt.2015.113.

AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington’s disease.

Connor B1, Sun Y1, von Hieber D1, Tang SK1, Jones KS1, Maucksch C1.
  • 1Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.



Reduced expression and disrupted corticostriatal transportation of brain-derived neurotrophic factor (BDNF) is proposed to contribute to the selective vulnerability of medium spiny striatal projection neurons (MSNs) in Huntington’s disease (HD). We have previously demonstrated that BDNF overexpression in the quinolinic acid lesioned rat striatum attenuates motor impairment and reduces the extent of MSN cell loss. To further investigate the potential therapeutic properties of BDNF for HD, the current study examines the effect of bilateral AAV1/2-mediated BDNF expression in the striatum of a transgenic rat model of HD. Transfer of the BDNF gene to striatal neurons using an AAV1/2 serotype vector enhanced BDNF protein levels in the striatum. Bilateral BDNF expression attenuated the impairment of both motor and cognitive function when compared with AAV1/2-vehicle- or YFP-treated transgenic HD rats. Interestingly, a gender effect was apparent with female transgenic HD rats exhibiting less functional impairment than males. Quantification of NeuN and DARRP32 immunoreactivity and striatal volume revealed limited disease phenotype between wild type and transgenic HD animals. However, AAV1/2-BDNF-treated transgenic HD rats showed evidence of greater striatal volume and increased NeuN+ cell numbers compared with wild-type vehicle- and AAV1/2-vehicle- or YFP-treated transgenic HD rats. We propose BDNF holds considerable therapeutic potential for alleviating behavioral dysfunction and neuronal degeneration in HD, with further work required to examine the role of BDNF-TrkB signaling and the preservation of axonal and synaptic function.

PMID: 26704721



Huntington’s disease (HD) is an inherited disease that causes the progressive death of specific populations of cells in the brain. The main cell population affected are the medium-sized spiny projection neurons found in the striatum of the brain. The loss of these cells results in patients experiencing motor disturbances together with cognitive and psychiatric dysfunctions. Typically, HD patients do not show any symptoms until onset at a median age between 35 and 42 years. HD progresses constantly until death occurs within 15 -20 years from the onset. Although the genetic mutation causing HD is known, our understanding of the pathogenesis is incomplete.  Currently, there is no therapy available to delay the onset of symptoms or the progression of HD, with only symptomatic treatment currently available to improve the quality of life for HD patients.

Brain-derived neurotrophic factor (BDNF) is a known survival factor for medium-sized spiny projection neurons in the striatum. It has been proposed that the genetic mutation in HD leads to a reduction in the production and transport of BDNF to medium-sized spiny projection neurons resulting in these cells being selectively vulnerable to neurodegenerative processes in the HD brain 1. Furthermore, BDNF levels have been shown to be reduced in post-mortem tissue from patients with HD 1.  These observations led us to investigate whether administration of BDNF to the HD brain could promote the survival of the medium-sized spiny projection neurons and thereby prevent or reduce impairments in motor and cognitive function. However, while BDNF may provide support for the medium-sized spiny projection neurons, difficulties in delivering BDNF to these cells in the brain may limit the true potential BDNF holds in counteracting the neurodegenerative process of HD. Indeed, the need for a continuous, long-term supply of BDNF across the entire striatum makes the delivery mechanism of central importance for the treatment of HD. We met this challenge by the use of an in vivo gene delivery system that allowed for continuous and targeted production of BDNF in the striatum, thereby ensuring long-term availability of BDNF to the selectively vulnerable medium-sized spiny projection neurons. We demonstrated that enhanced production of BDNF in the rat striatum prior to administration of the neurotoxin quinolinic acid, reduced the loss of medium-sized spiny projection neurons and attenuated motor impairment. Two papers describing the results of this work have been published 2, 3.

To further investigate the therapeutic potential of BDNF, we then examined the effect of BDNF in a genetic rat model of HD. We proposed that delivery of BDNF by gene therapy to the HD rat striatum prior to the onset of disease symptoms would increase the production of BDNF and therefore prevent the onset of both medium-sized spiny projection cell loss and functional impairment. The HD rat model was used as it provides a clinically relevant genetic animal model of HD, with progressive cell loss and functional impairment, in which to assess the therapeutic effect of BDNF. In this study, we also investigated whether there was any difference in the response of male and female rats to treatment with BDNF. The paper featured at this site describes these studies 4.

In agreement with our previous work, enhanced expression of BDNF in the HD rat model prevented both impairment of motor and cognitive function when compared to untreated or control treated HD animals. Furthermore, BDNF-treated HD rats showed evidence of reduced brain cell loss when compared with normal rats and with untreated or control treated HD animals. However, what was most prominent was the observed effect of gender both in the HD rat model and in response to BDNF treatment. Male HD rats demonstrated a greater level of impairment than female HD rats for both motor and cognitive function. Furthermore, female HD rats did not exhibit any cognitive deficit when compared to normal rats, and BDNF- treated female HD rats displayed enhanced motor function when compared to normal rats. We also observed an increase in body weight in BDNF-treated female rats that was not observed in male animals. These findings indicate that female HD rats are less affected by the disease and have a different response to BDNF treatment when compared to male rats.

The importance of the study is two-fold. First, it confirms the therapeutic potential of BDNF in the treatment of HD. For the first time, the study shows that BDNF gene therapy in a clinically relevant, genetic animal model of HD can prevent or reduce the progressive cell loss and clinical impairment of HD. As HD is a genetic disorder that can be identified in patients prior to the onset of clinical symptoms, pre-symptomatic delivery of BDNF via gene therapy is a highly viable strategy.

Second, this study demonstrates the need to investigate both male and female animals both in regards to disease phenotype and therapeutic response. As demonstrated in this study, both disease severity and the response of male versus female rats to BDNF differed significantly, indicating that gender is a factor that would need to be taken into consideration for any future clinical trials.



  1. Zuccato, C. & Cattaneo, E. Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81, 294-330 (2007).
  2. Kells, A.P., Henry, R.A. & Connor, B. AAV-BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment. Gene Therapy 15, 966-977 (2008).
  3. Kells, A.P. et al. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington’s disease. Molecular Therapy 9, 682-687 (2004).
  4. Connor, B. et al. AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington’s disease. Gene Ther (2016).






Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann