Simultaneous gene silencing and augmentation for restoration of BEST1-associated retinal degeneration

This technology is a combination of CRISPR/dCas9-mediated gene silencing and baculovirus-delivered gene augmentation to restore the healthy function of bestrophin-1 (BEST1) for the treatment of bestrophinopathies.

Unmet Need: Mutation-agnostic, therapies for BEST1-associated retinal degeneration

Mutations in the bestrophin-1 (BEST1) gene, which encodes a calcium activated channel, can result in a spectrum of retinal degenerative disorders collectively known as bestrophinopathies. Over 250 disease-causing BEST1 mutations have been identified, yet there are currently no available treatments. For loss-of-function mutations, introducing a functional copy of the gene is a feasible approach. However, traditional gene augmentation alone cannot overcome the strong dominant effects of gain-of-function mutations. Therefore, there remains a significant unmet need for a customizable method to manipulate BEST1 expression that caters to the specific genetic profile of individual patients.

The Technology: Customizable CRISPR/dCas9 gene silencing paired with gene augmentation to restore BEST1 function

This technology is a customizable method of combining gene augmentation with gene silencing to restore healthy function of BEST1. This targeted strategy effectively restores calcium-dependent chloride channel activity, providing a universal treatment option for both loss-of-function and gain-of-function BEST1 mutations.

This technology has been validated in HEK293 cells and human pluripotent stem cells.

Applications:

• Gene therapy for retinal degeneration
• Genetic models for retinal disease research
• Restoration of function for patients with loss-of-function and gain-of-function BEST1 mutations
• Research tool for characterizing ion channels in the retinal pigmented epithelium

Advantages:

• Universal treatment strategy
• Targets loss-of-function and gain-of-function mutations
• Precise suppression
• Patient-specific and highly customizable

Lead Inventor:

Stephen H. Tsang, MD, Ph.D.

Patent Information:

Patent Pending(US20240043848)

Related Publications:

• Zhao Q, Kong Y, Kittredge A, Li Y, Shen Y, Zhang Y, Tsang SH, Yang T. Distinct expression requirements and rescue strategies for BEST1 loss- and gain-of-function mutations. Elife. 2021 Jun 1;10:e67622.

• Ji C, Li Y, Kittredge A, Hopiavuori A, Ward N, Yao P, Fukuda Y, Zhang Y, Tsang SH, Yang T. Investigation and Restoration of BEST1 Activity in Patient-derived RPEs with Dominant Mutations. Sci Rep. 2019 Dec 13;9(1):19026.

Tech Ventures Reference:

• IR CU21170

• Licensing Contact: Kristin Neuman