Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule
Calvo, Ana Cristina (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)
Moreno Igoa, María (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)
Mancuso, Renzo (Universitat Autònoma de Barcelona. Institut de Neurociències)
Manzano Martínez, Raquel (Universidad de Zaragoza. Laboratorio de Genética Bioquímica)
Oliván, Sara (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)
Muñoz, María J. (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)
Penas Pérez, Clara (Universitat Autònoma de Barcelona. Institut de Neurociències)
Zaragoza, Pilar (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)
Navarro, X. (Xavier) (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Osta, Rosario (Universidad de Zaragoza. Laboratorio de Genética Bioquímica. Instituto Aragonés de Ciencias de la Salud)

Date:	2011
Abstract:	Background: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. Neurotrophic factors have been widely tested to counteract neurodegenerative conditions, despite their unspecific neuronal access. The non-toxic C-terminal fragment of the tetanus toxin (TTC) heavy chain has been studied not only as a carrier molecule to the CNS but also as a neuroprotective agent. Because the neurotrophic effects of BDNF have been demonstrated in vitro and in vivo, the question addressed in this work is whether a fusion molecule of BDNF-TTC may have a synergistic effect and enhance the neuroprotective properties of TTC alone in a mouse model of ALS. Methods. Recombinant plasmid constructs (pCMV-TTC and pCMV-BDNF-TTC) were injected into the quadriceps femoris and triceps brachialis muscles of SOD1 transgenic mice at 8 weeks of age. The hanging wire and rotarod tests were performed to assess motor coordination, strength and balance. Electrophysiological tests, morphological assays of spinal cord sections of L2 and L4 segments, and gene and protein expression analyses were performed. The Kaplan-Meier survival analysis test was used for comparisons of survival. Multiple comparisons of data were analyzed using a one-way analysis of variance (ANOVA). Results: Treatment with the fusion-molecule BDNF-TTC and with TTC alone significantly delayed the onset of symptoms and functional deficits of SOD1 mice. Muscle innervation was partially preserved with these treatments, and the number of surviving motoneurons in L2 spinal cord segment was increased particularly by the fusion protein induction. Inhibition of pro-apoptotic protein targets (caspase-3 and Bax) and significant phosphorylation of Akt and ERK were also found in the spinal cord of treated mice. Conclusions: Significant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival- activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effects.
Grants:	European Commission COST-B30/PI071133 Ministerio de Ciencia e Innovación FIS/SAF2009-12495
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Orphanet Journal of Rare Diseases, Vol. 6, Núm. 1 (2011) , p. 10, ISSN 1750-1172

Adreça alternativa: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-10
DOI: 10.1186/1750-1172-6-10
PMID: 21418619

16 p, 3.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
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Articles > Published articles