Precision Gene Therapy for Parkinson’s Disease: Targeted SNCA Down-regulation in Dopaminergic Neurons

Unmet Need

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting approximately 10 million people globally and 1 million in the U.S. PD is characterized by involuntary movements such as tremors, stiffness, and coordination challenges, which progressively worsen, severely impacting a patient’s quality of life. In addition to motor symptoms, PD can also lead to cognitive, behavioral, and emotional difficulties. Despite current treatments aimed at managing symptoms, there is currently no effective therapy that prevents or halts the progression of the disease. The degeneration of dopaminergic neurons and the accumulation of α-synuclein (encoded by the SNCA gene) are key drivers of PD. Elevated SNCA levels contribute to neuronal death, making it a validated therapeutic target. However, excessive reduction of SNCA can lead to neurotoxicity, necessitating precise regulation of SNCA expression in affected neurons. There is a need for a targeted, gene-editing approach to precisely regulate SNCA expression in dopaminergic neurons, offering a disease-modifying therapy that avoids harmful side effects.

Technology

Duke inventors have developed a therapeutic gene-editing system designed to target Parkinson’s disease. This is intended to be a disease-modifying therapy focused on treating PD diseases driven by SNCA dysregulation. Specifically, this therapeutic employs a novel epigenome-editing approach to selectively reduce SNCA expression in dopamine neurons, which are primarily affected in PD. By precisely targeting SNCA in these neurons, this therapeutic offers the potential to halt or even reverse disease progression. SNCA dysregulation is a key driver of dopamine neuron death, leading to the motor symptoms characteristic of PD. Unlike traditional treatments, which only manage symptoms, this therapy directly addresses the root cause of neuronal degeneration. It uses a gene-editing mechanism that ensures SNCA is precisely regulated within dopamine neurons without affecting other neuron types, maintaining the normal physiological functions required for brain health. This has been demonstrated through preclinical studies, where SNCA downregulation showed significant potential to prevent or even reverse dopamine neuron death in vivo. This represents a first-in-class disease-modifying therapy capable of altering the progression of PD, a breakthrough in a field where no such treatments currently exist.

Other Applications

This technology could also be applied to other neurodegenerative disorders where SNCA dysregulation plays a role, such as Alzheimer’s disease (AD), Lewy body disease (LBD), and Multiple System Atrophy (MSA).

Advantages

• Precisely targets SNCA expression in dopamine neurons, reducing off-target effects and ensuring specificity
• Offers the first disease-modifying therapy that may slow or stop Parkinson's disease progression
• Minimizes side effects by avoiding over-reduction of SNCA levels, protecting healthy neurons