Viral-mediated humanized mouse model for Parkinson’s disease

Unmet Need

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of α-synuclein aggregates (Lewy bodies), leading to motor and cognitive impairments. PD affects 1 to 2 out of every 100 individuals at any given time, with prevalence increasing significantly with age—impacting approximately 1% of the population over 60. In the United States alone, around 90,000 new cases are diagnosed each year. Despite its prevalence, there is no cure or treatment that halts disease progression. Most therapies involve managing symptoms, often with limited efficacy and considerable adverse side effects. Genetically engineered rodent models are used as a preclinical tool to study the underpinnings of disease progression in PD to develop effective therapeutics. However, current genetic mouse models fall short of fully replicating the complex pathology of PD in humans, particularly in mimicking α-synuclein expression, age-dependent neurodegeneration, and progressive symptom development. There is a need for better transgenic mouse models that more faithfully mirrors human PD pathophysiology to better support therapeutic discovery and translational research.

Technology

Duke inventors have developed a viral-mediated humanized mouse model that recapitulates hallmarks of Parkinson’s disease and other neurodegenerative diseases associated with α-synuclein pathologies. This is intended to be used by research laboratories studying PD pathogenesis and pharmaceutical companies involved in therapeutic development targeting α-synuclein pathologies. Specifically, the model uses an adeno-associated virus (AAV) carrying a minigene of the human A53T-mutant α-synuclein gene (hSNCA/A53T), driven by its native human SNCA promoter and intron 1 region. This construct, termed AAV-In1-hSNCA/A53T, enables physiologically relevant expression of α-synuclein and avoids the overexpression artifacts caused by strong, non-specific promoters like CMV, used in prior models. This has been demonstrated in C57BL/6 mice where the experimental viral group induced a 46-fold and 29-fold increase in human α-synuclein expression and aggregation respectively, as well as exhibited significant dopaminergic neuron loss and motor deficits over control groups, thus allowing better mechanistic understanding of human PD pathology in an in vivo murine model.

Advantages

• More clinically and translationally relevant for PD therapeutic targets.
• More accurately mimics human SNCA expression pattern during α-synuclein pathology.
• Better recapitulates disease-related cellular phenotypes such as neuronal viability, and mitochondrial dysfunction.