Novel Channelrhodopsins for Optogenetics Gene Therapy

When expressed in targeted neurons, light-sensitive channelrhodopsin proteins (ChRs) have the ability to selectively manipulate neuronal activity in a light-dependent manner. Gene therapy using anion ChRs (ACRs) has the potential for treating excessive neuron firing in conditions such as Parkinson’s disease, neuropathic pain and epilepsy, while cation ChRs (CCRs) hold promise for vision restoration.

Dr. John Spudich and his team at UTHealth have developed suites of ACRs and CCRs, which are orders of magnitude more efficient than currently available optogenetic tools and have the ability to effectively inhibit neuron firing for the treatment of neurodegenerative disease, neuropathic pain, ocular disorders, epilepsy, and cardiac disorders.

Technology Overview

• Anion channelrhodopsins (ACRs) that
  • Provide neuronal silencing
  • Hyperpolarize cultured animal cell membranes at < 1/1000 of the light intensity required by the most efficient currently available optogenetic protein
• Cation ChRs (CCRs) containing mutations of the transmembrane helix 4 with
  • Superior photocurrent amplitudes
  • Enhanced Na+ selectivity
  • Enhanced Ca2+ conductance
  • 

Stage of Development
Humanized ACRs have been successfully expressed in mammalian neurons, and have further been validated by a number of laboratories working in various animal systems, including the targeted silencing of neurons in the living mouse brain.  

Clinical Applications
Our ChRs have the potential to be used as gene therapy-based therapeutics for diseases caused by aberrant neuronal activity or other cellular excitation, such as neurodegenerative disease, neuropathic pain, ocular disorders, epilepsy, and cardiac disorders. 

Intellectual Property Status

Issued and pending patents (US and foreign) on suites of ACRs, CCRs and KCRs are available for licensing :

• US 9,676,836
• US 10,519,205
• CN107531765
• AU2016232819

Selected Publications

• Science. 2015 Aug7;349(6248):647-50. PMID: 26113638
• Annu Rev Biochem. 2017 Jun 20; 86: 845–872. PMID: 28301742
• eNeuro. 2018 Jul 10;5(3). ENEURO.0174-18.2018. PMID: 30027111
• Appl. Sci. 2019, 9(4), 664; doi:10.3390/app9040664
• Nat Neurosci. 2022 Jul; 25(7):967-974. PMID: 35726059

About the Investigator: Dr. John L. Spudich

• Professor of Department of Biochemistry and Molecular Biology ;
• Director of Center for Membrane biology;
• Robert A. Welch Distinguished Chair in Chemistry at UTHealth

UTHealth Ref. No.: 2011-0037 (CCR) & 2016-0030 (ACR) & 2022-0025 (KCR)