Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots

Eggers, Ruben; Hendriks, William T.; Tannemaat, Martijn R.; Heerikhuize, J.J. van; Pool, C.W.; Carlstedt, Thomas; Zaldumbide, Arnaud; Hoeben, Rob C.; Boer, G.J.; Verhaagen, Joost

doi:10.1016/j.mcn.2008.05.018

Cited by 87 publications

(120 citation statements)

References 50 publications

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“…[9][10][11] Among them, transduction of mouse and human Schwann cells has been achieved in vitro 12 and in vivo in animal models of peripheral nerve trauma. 13,14 With the aim to study whether AAV vectors are capable of specifically transducing Schwann cells, we tested the biodistribution of AAV1, AAV2 and AAV8 vectors following intraneural administration. Here, we demostrate that AAV8 mostly infects Schwann cells, whereas AAV2 has a unique tropism for sensory neurons, and AAV1 transduces both sensory neurons and Schwann cells when injected into the sciatic nerve of mice.…”

Section: Introductionmentioning

confidence: 99%

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

et al. 2011

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Efficient transduction of the peripheral nervous system (PNS) is required for gene therapy of acquired and inherited neuropathies, neuromuscular diseases and for pain treatment. We have characterized the tropism and transduction efficiency of different adeno-associated vectors (AAV) pseudotypes after sciatic nerve injection in the mouse. Among the pseudotypes tested, AAV2/1 transduced both Schwann cells and neurons, AAV2/2 infected only sensory neurons and AAV2/8 preferentially transduced Schwann cells. AAV2/8 expression in the sciatic nerve was detected up to 10 weeks after administration, the latest time point analyzed. The injected mice developed neutralizing antibodies against all AAVs tested; the titers were higher against AAV2/1 than AAV2/2 and were the lowest for AAV2/8, correlating with a higher transgene expression overtime. AAV2/8 coding for ciliary neurotrophic factor (CNTF) led to an upregulation of P0 and PMP22 myelin proteins, four weeks after transduction of injured sciatic nerves. Importantly, CNTF-transduced mice showed a significant increase in both GAP43 expression in sensory neurons, a marker of axonal regeneration, and the compound muscle action potential. These results prove the utility of AAV8 as a gene therapy vector for Schwann cells to treat myelin disorders or to improve nerve regeneration.

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Section: Introductionmentioning

confidence: 99%

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

et al. 2011

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“…Blockade of p75 with specific antibodies reverts the detrimental outcome induced by high doses of BDNF, and thus demonstrates a role of p75 in this effect [45]. Similarly to BDNF, GDNF can also support MN survival and regeneration [15,20,44,48]. In this case, mRNA levels of both GDNF receptors-high affinity receptor GFRa1 and low affinity receptor c-ret-increase in MN during some weeks after axotomy and avulsion lesions [44].…”

Section: Discussionmentioning

confidence: 96%

“…Similarly, application of exogenous GDNF [15,19,20] and BDNF [15,18] in the spinal cord after axotomy improves axonal regeneration. However, excessive levels of BDNF or GDNF, induced by gene vectors, may result in abnormal growth of axons, forming a neuroma at the site of the factor secretion [20]. It is plausible that stem cells provide a better regulation of neurotrophin levels by paracrine and autocrine mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…A subscale of the Basso, Beattie and Bresnahan (BBB) locomotor score [34] relevant for the lumbar root avulsion model was used for evaluating the hindlimb function, as described previously [3,20]. The voluntary movements of the ankle, knee, and hip joints of the avulsed limb were evaluated, with the scores for each being (0) = no spontaneous movement of the joint, (1) = slight movement of the joint and (2) = normal movement of the joint.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…In order to prevent MN death most studies have focused on the neuroprotective role of different neurotrophic factors. Thus, exogenous application of brain-derived neurotrophic factor (BDNF) [15,18] or glial cell line-derived neurotrophic factor (GDNF) [15,19,20] has been shown to partially promote survival of neurons and axonal regeneration after spinal root injuries. However, the efficacy of these factors depends on their continuous supply and periodic injections might be necessary.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

et al. 2013

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Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progressive death of segmental motoneurons (MN) leading to permanent paralysis. The chances for functional recovery after ventral root avulsion are very poor owing to the loss of avulsed neurons and the long distance that surviving neurons have to re-grow axons from the spinal cord to the corresponding targets. Following unilateral avulsion of L4, L5 and L6 spinal roots in adult rats, we performed an intraspinal transplant of mesenchymal stem cells (MSC) and surgical re-implantation of the avulsed roots. Four weeks after avulsion the survival of MN in the MSC-treated animals was significantly higher than in vehicle-injected rats (45 % vs 28 %). Re-implantation of the avulsed roots in the injured spinal cord allowed the regeneration of motor axons. By combining root re-implantation and MSC transplant the number of surviving MN at 28 days post-injury was higher (60 %) than in re-implantation alone animals (46 %). Electromyographic tests showed evidence of functional re-innervation of anterior tibialis and gastrocnemius muscles by the regenerated motor axons only in rats with the combined treatment. These results indicate that MSC are helpful in enhancing neuronal survival and increased the regenerative growth of injured axons. Surgical re-implantation and MSC grafting combined had a synergic neuroprotective effect on MN and on axonal regeneration and muscle re-innervation after spinal root avulsion.

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Functional motor recovery is improved due to local placement of GDNF microspheres after delayed nerve repair

Wood

Gordon

Kemp

et al. 2013

Biotech & Bioengineering

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The majority of bioengineering strategies to promote peripheral nerve regeneration after injury have focused on therapies to bridge large nerve defects while fewer therapies are being developed to treat other nerve injuries, such as nerve transection. We constructed delivery systems using fibrin gels containing either free GDNF or polylactide-glycolic acid (PLGA) microspheres with GDNF to treat delayed nerve repair, where ELISA verified GDNF release. We determined the formulation of microspheres containing GDNF that optimized nerve regeneration and functional recovery in a rat model of delayed nerve repair. Experimental groups underwent delayed nerve repair and treatment with GDNF microspheres in fibrin glue at the repair site or control treatments (empty microspheres or free GDNF without microspheres). Contractile muscle force, muscle mass, and MUNE were measured 12 weeks following treatment, where GDNF microspheres (2 weeks formulation) were superior compared to either no GDNF or short-term release of free GDNF to nerve. Nerve histology distal to the repair site demonstrated increased axon counts and fiber diameters due to GDNF microspheres (2 weeks formulation). GDNF microspheres partially reversed the deleterious effects of chronic nerve injury, and recovery was slightly favored with the 2 weeks formulation compared to the 4 weeks formulation.

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Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots

Cited by 87 publications

References 50 publications

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

Functional motor recovery is improved due to local placement of GDNF microspheres after delayed nerve repair

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