Therapeutic efficacy of AAV8-mediated intrastriatal delivery of human cerebral dopamine neurotrophic factor in 6-OHDA-induced parkinsonian rat models with different disease progression

Abstract

Parkinson’s disease (PD) is a progressive and age-associated neurodegenerative disorder. Patients at different stages of the disease course have distinguished features, mainly in the number of dopaminergic neurons. Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered neurotrophic factor, being deemed as a hopeful candidate for PD treatment. Here, we evaluated the efficacy of CDNF in protecting dopaminergic function using the 6-OHDA-induced PD rat model suffering from different levels of neuronal loss and the recombinant adeno-associated virus 8 (AAV8) as a carrier for the CDNF gene. The results showed that AAV8-CDNF administration significantly improved the motor function and increased the tyrosine hydroxylase (TH) levels in PD rats with mild lesions (2 weeks post lesion), but it had limited therapeutic effects in rats with severe lesions (5 weeks post lesion). To better improve the recovery of motor function in severely lesioned PD rats, we employed a strategy using the CDNF gene along with the aromatic amino acid decarboxylase (AADC) gene. This combination therapeutic strategy indeed showed an enhanced benefit in restoring the motor function of severely lesioned PD rats by providing the neuroprotective effect of CDNF and dopamine enhancing effect of AADC as expected. This study may provide a basis for future clinical application of CDNF in PD patients at different stages and offer a new alternative strategy of joint use of CDNF and AADC for advanced PD patients in clinical trials.

Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP+-Induced Cytotoxicity in vitro

“…Both CDNF and MANF belonged to the novel dopaminergic neurotrophic factor, which have the ability to protect dopamine neurons from death (Ren et al, 2013; Tereshchenko et al, 2014; Voutilainen et al, 2015; Garea-Rodríguez et al, 2016; Tang et al, 2017; Wang et al, 2017). For instance, after delivery of CDNF by adeno-associated virus type 2/8 into 6-OHDA treated rat striatum, it improved rat’s behavior deficit and restored TH positive dopaminergic neurons in substantial nigra and increased fiber density in striatum (Ren et al, 2013; Wang et al, 2017). In this study, we observed a larger amount of CDNF present in MenSCs-CM than GDNF.…”

Neuroprotective and reparative effects of endoplasmic reticulum luminal proteins – mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor

“…This could be due to the spreading of the protein since there was minimal coverage of the striatum in comparison with the protein without viral vector (20,24). Other studies have shown positive results with AAV-CDNF: both AAV2-CDNF (25) and AAV8-CDNF (26) showed positive effects, but the latter was a much milder lesion than in the previous studies.…”

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices

“…A flowchart of COMMAND is shown in Figure S4, along with examples of stereotaxic coordinates used by prior studies in Figure S5 (Aoi et al, 2000;Bilang-Bleuel et al, 1997;Cederfjä ll et al, 2015;Hattori et al, 1998;Horellou et al, 1994;Kilbourn et al, 1997;Kirik et al, 2000;Luo et al, 1999;Mandel et al, 1998;Rodrigues et al, 2003;Sacaan et al, 1991;Shults et al, 1996;Wang et al, 2017aWang et al, , 2017bZaczek et al, 1980).…”

“…Multi-bolus infusions improve control over spatial distribution, which reduces off-target toxicity. However, no standardized method to determine the optimal number, size, and location of boluses for a particular application exists (Cederfjä ll et al, 2015;Horellou et al, 1994;Kirik et al, 2000;Wang et al, 2017b).…”