NU 2024-086

INVENTORS

• Dalton J. Surmeier Jr*
• Weixing Shen
• Shenyu Zhai
• Tatiana Tkatch
• Qiaoling Cui
• Zhong Xie

SHORT DESCRIPTION

Gene therapy targeting GRIN2B in striatal spiny projection neurons to treat levodopa-induced dyskinesia.

BACKGROUND

Parkinson’s Disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer’s Disease, affecting nearly one million people in the U.S. Treatment with levodopa effectively alleviates the motor symptoms of PD. However, prolonged levodopa use can increase the risk of motor complications and loss of efficacy.

Levodopa-induced Dyskinesia (LID) is characterized by involuntary muscle movements resulting from fluctuating plasma Levodopa levels. Approximately 50% of patients develop LID after five years on levodopa, and 80–100% experience LID after ten years. Therefore, there is a strong need to limit the adverse motor symptoms caused by prolonged levodopa use.

ABSTRACT

Northwestern inventors have developed an adenoviral gene therapy system to suppress GRIN2B gene expression, which codes for the GluN2B subunit of NMDA receptors in striatal spiny projection neurons, to counteract the development and expression of LID while preserving the benefits of levodopa therapy. In preclinical studies, LID induction was correlated with an upregulation of GluN2B-containing NMDARs in striatal spiny projection neurons. Furthermore, viral-mediated knockdown of the GRIN2B subunit in animal models led to reduced LID-like features. Thus, this approach holds promise as a potential therapeutic strategy to slow PD progression in patients.

APPLICATIONS

• Treatment of Parkinson's Disease patients experiencing LID associated with prolonged levodopa use.

ADVANTAGES

• Specific targeting of NMDA receptors on striatal spiny projection neurons using a gene therapy approach.
• Decreases long-term dependence on levodopa for managing dyskinesia.

PUBLICATIONS

Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia. Weixing Shen, Shenyu Zhai, Veronica Francardo, Qiaoling Cui, Zhong Xie, Tatiana Tkatch, M. Angela Cenci, D. James Surmeier. bioRxiv 2024.06.14

IP STATUS

US Patent Pending