In this issue, we introduce the genetically humanized SNCA model - B6-hSNCA mouse (product number: C001427), providing a next-generation humanized mouse model for drug discovery for the key therapeutic target of Parkinson's Disease (PD) & Dementia with Lewy Bodies (DLB). Let's first learn about Parkinson's Disease (PD) and the SNCA gene.

Parkinson's Disease Dementia

There are two types of Lewy body dementia — dementia with Lewy bodies and Parkinson's disease dementia — which are caused by the same underlying neurodegenerative changes in the brain. Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects the middle-aged and elderly population, being the second most common neurodegenerative disease after Alzheimer's Disease (AD). Its main characteristic is the gradual loss of dopaminergic neurons in the brain, leading to symptoms such as tremors, stiffness, and difficulty in movement. According to the Parkinson's Foundation, over 10 million people worldwide suffer from PD, and the incidence is expected to double in the next 30 years.[1] PD presents heterogeneity in clinical manifestations, pathological features, and genetic traits yet can be categorized into rapidly progressive and slowly progressive types. However, regardless of the type, there is currently no cure, and patients can only receive symptomatic treatment to improve motor and non-motor symptoms.[2]

Figure 1. Age-standardized prevalence of Parkinson's Disease per 100,000 people in different regions around the world.[3]

Genetic Mechanisms of Parkinson's Disease (PD)

Although Parkinson's Disease (PD) has been clinically recognized for over 200 years and its pathological descriptions date back more than 100 years, a comprehensive understanding of the disease still requires further exploration. Risk factors for PD include age, gender, exposure to pesticides, traumatic brain injury, and family history. Its main pathological mechanism involves dysfunction of the basal ganglia, a group of interconnected subcortical nuclei and brainstem nuclei that play a critical role in initiating and smoothly executing movement. Specifically, the loss of dopaminergic neurons in the substantia nigra impacts signal transmission to the striatum (composed of the caudate nucleus and globus pallidus), leading to substantia nigra hypoplasia (underdevelopment). From a genetic perspective, since the discovery of SNCA, the first gene associated with PD, more than 100 different genes have been identified with a clear association to PD susceptibility over the past two decades.[4]


Figure 2. Advances in Genetic and Therapeutic Research on Parkinson's Disease.[5]

SNCA Gene Mutations and Parkinson's Disease

The typical clinical presentation of Parkinson's Disease (PD) includes specific motor phenotypes, characterized by the formation of Lewy bodies and the loss of neurons in the substantia nigra. The pathological process of the disease primarily involves the formation of Lewy bodies (LB) in the central nervous system, leading to the gradual death and loss of dopaminergic neurons. Lewy bodies are mainly composed of insoluble aggregates of abnormal alpha-synuclein (α-syn). The SNCA gene, which codes for alpha-synuclein, was the first gene discovered to be associated with PD and is considered one of the key pathogenic genes in the disease. Mutations in the SNCA gene can lead to overexpression of alpha-synuclein (α-syn), resulting in the formation of Lewy bodies. This pathology is widely present in the central and peripheral nervous systems of patients with PD, ultimately leading to the development of the disease.[6-7] Therefore, the SNCA gene and alpha-synuclein (α-syn) are considered effective targets for the treatment of PD.

Figure 3. Mutations in the SNCA Gene and Other Related Genes Leading to Parkinson's Disease (PD).[7]

Targeting SNCA for the Treatment of Parkinson's Disease

Because alpha-synuclein (α-syn) is an intrinsically disordered protein lacking a typical small molecule binding pocket, traditional small molecule drug therapies face significant challenges. New therapeutic strategies are primarily focused on inhibiting the excessive formation of alpha-synuclein, degrading alpha-synuclein, or preventing its aggregation to halt the formation of Lewy bodies (LB). These strategies include gene therapy targeting the SNCA gene or SNCA mRNA, ribonuclease-targeting chimeras (RIBOTACs), small nucleic acid drugs (such as ASOs, siRNAs, and miRNAs), and antibody drugs targeting the protein.[8-12] Regardless of the approach, precise targeting of human genes or proteins is necessary. Thus, preclinical models expressing the humanized SNCA gene are essential in the development of therapies targeting the SNCA gene. The development and application of these models undoubtedly bring new possibilities for the treatment research of Parkinson's Disease.

Figure 4. Different Strategies for Targeting the SNCA Gene or Alpha-Synuclein (α-syn) in the Treatment of Parkinson's Disease.[12]

Mouse Models for Preclinical Research on SNCA Targeted Therapies

In 2022, Ionis Pharmaceuticals developed an SNCA-targeted antisense oligonucleotide (ASO) therapy named ION464, which was approved to enter Phase I clinical trials.[13] In preclinical studies, wild-type (WT) SNCA-PAC mice, expressing the human WT SNCA gene, were used to validate the drug's inhibitory effect on the formation of alpha-synuclein (α-syn). The results showed that ION464 could inhibit the production of alpha-synuclein, prevent neuronal death after exposure to toxic alpha-synuclein fibers, and alleviate pathological phenotypes and motor deficits.[14] Additionally, various mouse models expressing human wild-type or mutant SNCA genes, such as Thy1-SNCA mice, TH-SNCA-140 m mice, and α-syn A53T mice, were also used to evaluate the inhibitory effects of SNCA-targeted ASOs and other small nucleic acid drugs on the formation of alpha-synuclein in the central nervous system.[15-18]

Figure 5. PEI/SNCA-siRNA Nanoparticles Significantly Reduce SNCA mRNA and Protein Expression in the Brains of Thy1-aSyn Mice.[18]

Humanized SNCA Gene Model: B6-hSNCA Mice

To meet the urgent need for new therapies for Parkinson's disease, Cyagen can provide various transgenic, point-mutated, or humanized mouse and rat models for preclinical research, especially in the field of SNCA-targeted gene therapy or small nucleic acid drugs. Among these, the B6-hSNCA mouse (Product Code: C001418) is a humanized mouse model created by gene editing technology that replaces the mouse Snca gene in situ with the human SNCA gene, successfully expressing the human SNCA gene without expressing the endogenous mouse Snca gene. Additionally, we can also construct humanized models with prevalent pathogenic point mutations based on this model to meet the needs of emerging therapies such as CRISPR, ASOs, siRNAs, and miRNAs.

Figure 6. Detection of Gene Expression in Wild-Type Mice (WT) and B6-hSNCA Mice (hSNCA).

Conclusion

The B6-hSNCA mouse model (Product Code: C001427) is capable of effectively expressing the human SNCA gene without expressing the endogenous mouse Snca gene. There is significant expression of the human gene in both the brain and spleen. Therefore, the B6-hTARDBP mouse model can be used to study neurodegenerative diseases related to the SNCA gene, such as Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore, Cyagen can provide disease models with popular point mutations based on this model, and offer customized services according to different point mutations to meet the extensive research and development needs for related drug screening and pharmacology studies.

Despite their popularity, common humanized models — including transgenic (Tg) mice, coding sequence (CDS), and single-exon humanized mice — fall short in achieving full human gene integration into the mouse genome. To advance our understanding of disease mechanisms and drug development, there is a pressing need for full-length genomic DNA humanized mice. These models can faithfully replicate human gene expression patterns, regulations, and functional properties in a mouse model.

Cyagen has developed the first full-length genomic sequence humanized mouse models now available through our HUGO-GT™ (Humanized Genomic Ortholog for Gene Therapy) program. We employ our proprietary TurboKnockout-Pro technology to perform in-situ replacement of the targeted mouse endogenous gene, which aims to better replicate human gene expression patterns, regulations, functional properties, and a broader range of intervention targets in a mouse model. We have begun establishing HUGO-GT mouse models to study other neurodegenerative and rare diseases such as Frontotemporal Dementia (FTD), Spinal Muscular Atrophy (SMA), and Amyotrophic lateral sclerosis (ALS).

>> Explore our HUGO-GT™ Next-Generation Humanized Models

 

References:
[1]Parkinson’s Foundation. (n.d.). Understanding Parkinson’s: Statistics. Retrieved January 20, 2024, from https://www.parkinson.org/understanding-parkinsons/statistics
[2]Bloem BR, Okun MS, Klein C. Parkinson's disease. Lancet. 2021 Jun 12;397(10291):2284-2303.
[3]GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018 Nov;17(11):939-953.
[4]Dumbhare O, Gaurkar SS. A Review of Genetic and Gene Therapy for Parkinson's Disease. Cureus. 2023 Feb 5;15(2):e34657. 
[5]Dong-Chen X, Yong C, Yang X, Chen-Yu S, Li-Hua P. Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023 Feb 21;8(1):73.
[6]Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020 Feb 11;323(6):548-560.
[7]Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson's Syndrome. Annu Rev Pathol. 2023 Jan 24;18:95-121.
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[9]Polissidis A, Petropoulou-Vathi L, Nakos-Bimpos M, Rideout HJ. The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson's Disease. Biomolecules. 2020 Jun 16;10(6):912.
[10]Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A, Olanow CW, Merchant KM, Bezard E, Petsko GA, Meissner WG. Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol. 2015 Aug;14(8):855-866.
[11]Tong Y, Zhang P, Yang X, Liu X, Zhang J, Grudniewska M, Jung I, Abegg D, Liu J, Childs-Disney JL, Gibaut QMR, Haniff HS, Adibekian A, Mouradian MM, Disney MD. Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera. Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2306682120.
[12]Bortolozzi A, Manashirov S, Chen A, Artigas F. Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson's disease. Pharmacol Ther. 2021 Nov;227:107873. 
[13]Alzforum. (n.d.). Therapeutics: ION464. Retrieved January 20, 2024, from https://www.alzforum.org/therapeutics/ion464
[14]Cole TA, Zhao H, Collier TJ, Sandoval I, Sortwell CE, Steece-Collier K, Daley BF, Booms A, Lipton J, Welch M, Berman M, Jandreski L, Graham D, Weihofen A, Celano S, Schulz E, Cole-Strauss A, Luna E, Quach D, Mohan A, Bennett CF, Swayze EE, Kordasiewicz HB, Luk KC, Paumier KL. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI Insight. 2021 Mar 8;6(5):e135633.
[15]Alarcón-Arís D, Recasens A, Galofré M, Carballo-Carbajal I, Zacchi N, Ruiz-Bronchal E, Pavia-Collado R, Chica R, Ferrés-Coy A, Santos M, Revilla R, Montefeltro A, Fariñas I, Artigas F, Vila M, Bortolozzi A. Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson's Disease. Mol Ther. 2018 Feb 7;26(2):550-567.
[16]Yang J, Luo S, Zhang J, Yu T, Fu Z, Zheng Y, Xu X, Liu C, Fan M, Zhang Z. Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease. Neurobiol Dis. 2021 Jan;148:105218.
[17]Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, Baba K, Nagata T, Yokota T, Tsuda H, Obika S, Mochizuki H. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson's disease. Sci Rep. 2019 May 21;9(1):7567.
[18]Helmschrodt C, Höbel S, Schöniger S, Bauer A, Bonicelli J, Gringmuth M, Fietz SA, Aigner A, Richter A, Richter F. Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson's Disease. Mol Ther Nucleic Acids. 2017 Dec 15;9:57-68. 

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