Extracellular Vesicles-Mediated Delivery of CRISPR Machinery for Inhibiting Prostate Cancer
Abstract
Prostate cancer is the second leading cause of cancer-related deaths for men. There are about 1.4 million new cases of prostate cancer globally. About 3.2 million people are living with prostate cancer in the U.S. The current treatment primarily relies on using chemical compounds to inhibit the activity of a major oncogene, called androgen receptor (AR) activity, thereby inhibiting prostate cancer progression. Anti-androgen or AR signaling agents, such as the second-generation of AR inhibitors enzalutamide and abiraterone, have been developed for prostate cancer treatment. However, multiple molecular mechanisms have emerged to maintain AR signaling leading to drug resistance. As a result, the proliferation of a majority of prostate cancer cells is still maintained through AR signaling by responding to either a very low amount of androgen or by constitutively active AR mutants. These patients no longer benefit from current androgen deprivation therapy and are usually treated with chemotherapy (which has many side effects and often a low survival rate). Currently, 10-20% of the prostate cancer population will develop disease that is castration-resistant within 5 years. The median survival of patients with castration-resistant prostate cancer (CRPC) is about 9-30 months. Progression to CRPC affects quality of life, and few therapeutic options are available for CRPC patients. There is an urgent need to provide additional therapeutic options for treatment of the CRPC. CRISPR technology holds great promise in genome editing for gene therapy. However, reliable and efficient delivery of the CRISPR machinery in vivo remains the primary challenge to implementing this potentially transformative technology. The overall objective of this study is to develop a novel technology that will encapsulate the genomic editing CRISPR machinery into extracellular vesicles (EVs). EVs are biological nanoparticles that are secreted by almost all cell types. A large body of studies has shown that EVs mediate cell- to-cell communication by transmitting their encapsulated contents. Therefore, EVs are naturally produced by the body and serve as biological delivery vehicles. EVs can enter the circulatory system and release their contents to regulate the physiological state of recipient cells in a distant organ. In this study, the investigators will genetically modify the CRISPR/Cas9 protein. The modification will allow CRISPR machinery to be packed into EVs. Additionally, the investigators will engineer the membrane of EVs to target prostate cancer cells preferentially. This engineered delivery system will preferentially silence the androgen receptor gene in prostate cancer cells, thereby inhibiting the growth of prostate tumors. In contrast to the current treatment strategy to inhibit AR activity with chemotherapy, the distinctive proposition of this technology is deleting the AR gene at the DNA level in prostate cancer cells, thereby inhibiting the growth of prostate tumors while minimizing unfavorable side effects associated with chemotherapy. This novel technology will eliminate numerous molecular mechanisms leading to castration-resistance in prostate cancer. Of note, if successful, the technology could also be used to silence other oncogenes in androgen receptor negative prostate cancer cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310086
Entities
People
- Houjian Cai
Organizations
- The University of Georgia
- United States Army