420. Hydrodynamic Limb Vein Delivery of Naked IGF-1 Plasmid DNA Provides Therapeutic Benefit in SOD1(G93A) Murine ALS Model
Year: 2006
Type: article
Abstract: Motor neuron degeneration and death in ALS can be mitigated by neurotrophic factors. A number of neurotrophic factors (e.g., VEGF, GDNF and IGF-1) have been demonstrated to promote survival and regeneration of motor neurons both in vitro and in vivo. An increase in the lifespan of SOD1 mice was observed following delivery of viral vectors expressing GDNF or IGF-1. For human gene therapy, a non-viral approach would be preferred. Recently, highly effective transfer of plasmid DNA expression vector to skeletal muscle was described using hydrodynamic delivery of pDNA solutions into limb veins. This method promises a safe non-viral gene therapy route that is equally effective in small and large research animals. Here we determined if IGF-1 expression vectors delivered by the hydrodynamic limb procedure can alter the clinical course of disease in SOD1(G93A) mice. An expression vector was generated in which the human IGF-1 cDNA was under transcriptional control of the human CMV promoter. The plasmid DNA was injected into 6- week old SOD1 mice (prior to the onset of disease symptoms) in both hind limbs. For the plasmid DNA deliveries, the hind limbs were temporarily isolated by the placement of a tourniquet. The plasmid DNA solution (1.0 ml) was subsequently delivered into the saphenous vein at a rate of 0.17 ml/sec. The tourniquet was released after 2 minutes. SOD1 mice treated with IGF-1 lived 28 days longer (138 ± 4.5 days) than untreated SOD1 mice (110.1 ± 5.2 days). This improvement in survival was equal if not better than after adeno- associated virus vector IGF1 gene transfer. IGF-1 and reporter gene expression was detected from injected muscles but not in the sera or spinal cords at end-point of the experiments. The motor performance (RotaRod) declined less rapidly in the IGF-1 injected SOD1 mice than in the controls. These data suggest that hydrodynamic limb vein plasmid DNA transfer of IGF-1 had a beneficial therapeutic effect for SOD1 mice. It is most likely that this effect was due to target-derived functions of IGF-1 originating from muscle expression (i.e., retrograde transport of IGF-1 protein from the site of production in the muscle tissue to the motor neuron body). This technique has promise for treatment of ALS.
Source: Molecular Therapy
Language: German
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2083048728