Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure

“…Viral vectors such as lentivirus, adenovirus, and adeno-associated viral vectors are widely used, mainly because they are highly efficient in introducing target genes into host cells. Compared with adenovirus and adeno-associated viral vectors, lentivirus possesses the ability to transport larger gene fragments thus ensuring earlier protein expression [31]. As a result, lentivirus is an attractive gene delivery system and is widely used in gene therapy [32].…”

Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

“…Therefore the potential effectiveness of BMP therapies declines as the disease progresses, and thus methods that ensure a sustained and targeted supply of these agents to nigrostriatal dopaminergic neurons must be developed. One such approach under investigation is gene therapy, which aims to introduce a long-term source of neurotrophic proteins to the brain, and which has shown promise for PD (for review see [19]). Gene therapy using viral vectors to achieve an adequate supply of BMPs to degenerating nigrostriatal neurons in the PD brain may be an optimal way of ensuring clinical efficacy, even in advanced disease states.…”

“…Given the lack of efficacy of AAV-NTN to date [21] and the fact GDNF ligands may not be able to signal in the PD brain due to down-regulation of Ret [22], it has recently been suggested that 'better results might be achieved with other trophic factors that are not Ret dependent' and that 'it might also be of value to assess trophic factors in animal models that overexpress α-synuclein prior to initiating translational clinical trials' [21]. Given that BMP ligands have the same efficacy as GDNF in 6-OHDA animal models of PD [18,19], and that their effects on mDA neurons are mediated in a Ret-independent manner through the Smad pathway [34], it will be crucial to determine if BMPR expression or key downstream effector proteins are affected by α-synuclein, and if the BMP ligands can exert neuroprotective effects in the α-synuclein model of PD. It is interesting to note that BMP2 has also recently been shown to up-regulate Nurr1 [86], raising the intriguing possibility that BMP ligands may restore responsiveness to the GDNF ligands, and highlighting the potential for combined neurotrophic factor therapy to protect mDA axons as well as their neuronal soma.…”

“…Several members of the transforming growth factor-β (TGFB) superfamily are potent neurotrophic factors for mDA neurons [18]. These include glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), which have been tested in clinical trials [19]. Despite initial promising results, these trials have not to date been successful [20,21].…”

Effects of intracerebral neurotrophic factor application on motor symptoms in Parkinson's disease: A systematic review and meta-analysis

“…Several NTFs promote the survival and growth of midbrain DA neurons in vitro and in vivo, while glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) have been used in PD clinical trials [8][9][10]. These NTFs have been delivered to the PD brain via various delivery methods, to distinct target region(s), in small-and largerscale clinical trials.…”