Objective: Our objective is twofold: 1)to examine whether CDNF-ASO paradigm can induce a unique phenotype mimicking PD/PDD/LBW in the rodent species; 2) to evaluate whether in the 6hydroxydopamine(6-OH-DA) PD model , differential changes in the CDNF mRNA expression occur in the striatum/ substantia nigra (S-SN).
Background: Growing evidence suggests targeting CDNF as the gatekeeper of endoplasmic-reticulum-stress in unfolded-protein-response (UPR) and alpha-synclein(SYN) aggregation, can be beneficial in PD and PD-dementia and Lewy Body Dementia (LBD).We hypothesize that CDNF gene inactivation can accelerate PD/PDD/LBW via SYN aggregation and self-propagation
Method: We formulated ASO sequence (intergrated DNA technologies (Iowa USA) to target CDNF gene capped with phosphorothiorate (*):5’T*T*T*C*C*C*T*T*G*G*T*G*T*C*C*G*C*G*A3’ to prevent nuclease degradation.MaleSprague Dawley rats underwent stereotaxic infusion a:1 mM ASO-CDNF via Alzet-osmotic pump to striatum for 14 days(n=8). Control group was infused with artificial/Cerebral-spinal-flud(CSF) : aCSF group ( n=8). We monitor exploratory open-field locomotor activity with AccuScan cages(OH-USA) for milieu habituation/motor activity at baseline, day7/day14 . For gait balance and motor coordination, we used the beam walk test and the Neurological Rating scale(NRS). For unilateral 6-OD-DA model, we compared CDNF mRNA expression in sSN (n=8)in right versus-left S-SN as measured with immunoblotting and qRT-PCR .
Results: Result: We found the ASO-CDNF group exhibited significant increase in locomotor activity compared with the aCSF group at 14 days (P <0.001; two-way ANOVA p< 0.0002), showing impaired cognition related to habituation deficits to cues and locomotor hyperactivity.Significant worsening in neurological performance in the NRS score at 7 days (p<0.05 and 14 day (p<0.01) occurred in ASO-CDNF group versus aCSF group. No significant changes in CDNF mRNA expression in ASO-CDNF group. CDNFmRNA expression was insensitive in the 6-OH-DA PD model.
Conclusion: We demonstrate that transient and partial CDNF gene inactivation mimics PD/PDD/LBD phenotype , implicating relevance of CDNF in driving endoplasmic reticulum-modulated SYN UPR . ASO-guided CDNF-mimetics, targeting anti-SYN can be potential disease-modifying gene therapy in PD/PDD/LBD.
References: Henri J Huttunen 1 2 , Mart Saarma 3 CDNF Protein Therapy in Parkinson’s Disease Cell Transplant 2019 Apr;28(4):349-366. doi: 10.1177/0963689719840290. Epub 2019 Apr 4. Voutilainen MH, Arumäe U, Airavaara M, Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015 Dec 21;589(24 Pt A):3739-48. doi: 10.1016/j.febslet.2015.09.031. Epub 2015 Oct 9. PMID: 26450777 Jӓntti M, Harvey BK. Trophic activities of endoplasmic reticulum proteins CDNF and MANF. Cell Tissue Res. 2020 Oct;382(1):83-100. doi: 10.1007/s00441-020-03263-0. Epub 2020 Aug 26. PMID: 32845431 Review. Scoles DR, Pulst SM. Antisense therapies for movement disorders.Mov Disord. 2019 Aug;34(8):1112-1119. doi: 10.1002/mds.27782. Epub 2019 Jul 8. PMID: 31283857 Review.
To cite this abstract in AMA style:
SS. Chiu, K. Terpstra, RK. Mishra. Pilot study of Phenotype of Antisense-Oligonucleotide-(ASO)-knockdown of Cerebral-Dopamine-Neurotrophic-Factor (CDNF) as Parkinson Disease model : implications for PD and related Dementia Therapeutics [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/pilot-study-of-phenotype-of-antisense-oligonucleotide-aso-knockdown-of-cerebral-dopamine-neurotrophic-factor-cdnf-as-parkinson-disease-model-implications-for-pd-and-related-dementia-therapeutics/. Accessed November 22, 2024.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/pilot-study-of-phenotype-of-antisense-oligonucleotide-aso-knockdown-of-cerebral-dopamine-neurotrophic-factor-cdnf-as-parkinson-disease-model-implications-for-pd-and-related-dementia-therapeutics/