Gene therapy with AAV2‐CDNF provides functional benefits in a rat model of Parkinson's disease

Abstract

Cerebral dopamine neurotrophic factor (CDNF) protein has been shown to protect the nigrostriatal dopaminergic pathway when given as intrastriatal infusions in rat and mouse models of Parkinson's disease (PD). In this study, we assessed the neuroprotective effect of CDNF delivered with a recombinant adeno-associated viral (AAV) serotype 2 vector in a rat 6-hydroxydopamine (6-OHDA) model of PD. AAV2 vectors encoding CDNF, glial cell line–derived neurotrophic factor (GDNF), or green fluorescent protein were injected into the rat striatum. Protein expression analysis showed that our AAV2 vector efficiently delivered the neurotrophic factor genes into the brain and gave rise to a long-lasting expression of the proteins. Two weeks after AAV2 vector injection, 6-OHDA was injected into the rat striatum, creating a progressive degeneration of the nigrostriatal dopaminergic system. Treatment with AAV2-CDNF resulted in a marked decrease in amphetamine-induced ipsilateral rotations while it provided only partial protection of tyrosine hydroxylase (TH)-immunoreactive cells in the rat substantia nigra pars compacta and TH-reactive fibers in the striatum. Results from this study provide additional evidence that CDNF can be considered a potential treatment of Parkinson's disease.

Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

“…As a control, we used AAVs carrying GFP. Production of the AAV2-CDNF and AAV2-GFP viruses used in this study has been described previously in detail [10]. Briefly, a cDNA-encoding human CDNF was cloned into pAAV-MCS vector (Stratagene).…”

“…This was achieved by using adeno-associated-viruses (AAV) for human CDNF gene transfer [10]. As a control, we used AAVs carrying GFP.…”

“…For instance, BDNF levels are reported to decrease in Alzheimer's disease (AD) inflicted brains [1,2] and A newcomer in the neurotrophic factor field is CDNF which has displayed strong neuroprotective and neurorestorative effects in animal models of Parkinson's disease (PD). CDNF can protect dopaminergic cells in the 6-OHDA rat model [10,11] and the MPTP mouse model [12] when given prior to lesioning but also when administered weeks after the lesion. CDNF and related protein mesencephalic astrocyte-derived neurotrophic factor (MANF) also regulate endoplasmic reticulum (ER) stress and unfolded protein response (UPR) [13].…”

Improving miRNA Delivery by Optimizing miRNA Expression Cassettes in Diverse Virus Vectors

“…[70][71][72][73][74] As with other integrating vectors, insertional mutagenesis remains a concern, especially for rAAV that lacks the specificity for chromosome 19. Wild-type AAV and rAAV integration has been linked to hepatocellular carcinoma in mice due to insertional oncogene activation, [75][76][77] but other long-term studies did not describe such a correlation.…”

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

“…This is probably due to different distribution patterns of the proteins, as GDNF immunoreactivity was widespread, whereas CDNF was detected only within cells (Ref. 54). Intraneuronal confinement of CDNF protein following AAV-mediated delivery is probably the reason for the lack of neuronal sprouting, since such sprouting was found following infusion of CDNF protein into the striatal parenchyma (Ref.…”