CRISPR-Cas9 Gene Therapy for ALS Enhanced by TJ-Targeted Barrier Modulation
Abstract
What type of ALS patients will it help, and how will it help them? This study has the potential to first treat inherited ALS patient with SOD1 mutation. The study is a preclinical development using a small animal model to demonstrate the enhanced efficacy of CRISPR-Cas9 based gene therapy, which has high efficiency and specificity for disrupting the disease-driving genes. The success of the project will encourage future attempts to edit other ALS-related therapeutic genes (such as C9orf72). Due to the high translational value encouraged by recent clinical trials and FDA approval for treating human patients, gene therapy has potential as the lifesaving drug for inherited ALS. What are the potential clinical applications, benefits, and risks? Potentially, light stimulation to overcome the barriers in the brain and spinal cord can be translated to the clinic to deliver therapeutics, such as gene therapy, to local or global regions affected by ALS in treating this deadly disease. Gene therapy represents a single-dose, long-lasting drug and has the potential to permanently cure inherited ALS if used at the right time and under the right conditions. The basic benefits include the delay of onset, slowing progression, improving motor function, and prolonging survival. Potential risks include the high dose of laser light and viral vector required for achieving sufficient therapeutic benefit can lead to side effects and liver toxicity. In this project, we aim to significantly reduce the dose of light and the viral dose needed and to maximize the benefit with a single reduced dose administration. Gold nanoparticles needed by this technology for arching the molecules on the vessel are mostly safe, based on published data, but still need to be carefully investigated in follow-up studies. What is the projected time it may take to achieve a patient-related outcome? If this project is successful, the next step will be to test in large animals to establish efficacy and safety, which can be completed in another 2 to 3 years. Upon success at that stage, the data can be submitted to the U.S. Food and Drug Administration for approval for clinical translation; that may take 1 to 2 years. Ultimately, we project the first human patient could potentially receive this treatment 5 to 6 years later upon success in preclinical studies. What are the likely contributions of this study in advancing the development of therapeutics for ALS? An efficient and safe method for effectively delivering gene therapy, and other therapeutics restricted by the BBB/BSCB for ALS treatment. The high delivery efficiency will significantly reduce the dose of the therapeutics needed, thus will greatly reduce the risk and side-effects. While this study focuses on SOD1 mutation as proof-of-concept, the delivery technology has the potential to treat other ALS mutations, such as C9orf72 and FUS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110219
Entities
People
- Zhenghong Gao
Organizations
- United States Army
- University of Texas at Dallas