The fight against pancreatic cancer remains an enormous challenge due to the complex and varied nature of the disease. Scientists have been looking for better ways to deliver therapeutic genes into cancer cells effectively. One promising approach involves using viruses to transport these genes into cells. However, it has been difficult to find the right virus that can consistently deliver genes to all the different subtypes of pancreatic ductal adenocarcinoma (PDAC). This is where the Sendai virus shows exceptional promise, offering a robust and efficient way to overcome these challenges.
Researchers at Oregon Health and Science University, led by senior author Dr. Jungsun Kim and colleagues, including first author Dr. Dmytro Grygoryev, have shown that Sendai virus (SeV) is a vector robust and efficient to introduce genes into PDAC cells. Their findings, published in the peer-reviewed journal Heliyon, show that the Sendai virus outperforms others in terms of transduction efficiency, making it a promising tool for gene therapy in PDAC.
PDAC is known for its low survival rates, with the five-year survival rate being the lowest among all cancers. This is partly due to the lack of early symptoms and non-invasive markers that could facilitate early diagnosis. Understanding the molecular mechanisms of PDAC and identifying new therapeutic targets are essential to improve patient outcomes. PDAC can be grouped into two main transcriptional subtypes “classic” and “basal, squamous or mesenchymal”, and shows high inter- and intratumoral heterogeneity. Therefore, it is important to administer transgenes to all subtypes consistently.
The team noted that the lentivirus transduces certain subtypes of PDAC or normal cells in the patient-derived culture. This observation has motivated researchers to compare the transduction efficiencies of several vectors, including vesicular stomatitis virus glycoprotein G-pseudotyped lentiviral vectors (VSV-G) and adeno-associated viral (AAV) vectors, in both normal pancreatic ductal cells. as in patient-derived PDAC cells. The results consistently favored the Sendai viral vector in different PDAC subtypes, demonstrating its robust performance regardless of cell type. Dr. Kim stated, “The Sendai virus vector provided the most robust gene delivery efficiency regardless of PDAC subtypes. “This makes it a valuable tool for gene-based therapeutic strategies.”
The study also highlights the limitations of other viral vectors. For example, lentiviral vectors showed variable transduction efficiencies depending on the PDAC cell type, with poor performance in classical subtype PDAC cells. Similarly, AAV vectors, although widely used, have several shortcomings, including the need for high doses and limited genomic packaging capabilities. On the contrary, the Sendai virus, being an RNA virus, replicates in the cytoplasm without integrating into the host's genome, thus avoiding possible genomic alterations.
Sendai virus offers a non-integrative approach to gene delivery, which is advantageous for maintaining the genetic integrity of host cells. Another important advantage of Sendai virus is its ability to maintain transgene expression in highly dividing cells for a prolonged period, up to five passages. This is particularly beneficial for long-term studies and therapeutic applications where sustained gene expression is crucial. “Our findings suggest that Sendai virus is an efficient RNA-based gene delivery vehicle, capable of long-lasting transgene expression in PDAC and normal pancreatic ductal cells,” added Dr. Kim.
The implications of this study are enormous, especially for the development of gene therapies for pancreatic cancer. The high transduction efficiency of Sendai virus also makes it suitable for genome-wide genetic screens, which require a low multiplicity of infections per cell. Furthermore, the safety profile of Sendai virus, which has never been linked to human disease, further enhances its potential for cell therapy, such as in vivo transdifferentiation or direct reprogramming in pancreatic diseases.
Despite the promising results, the researchers recognize the need for further research to determine the extent of toxicity and efficacy in vivo, particularly in murine models where Sendai virus cannot be used due to its pathogenicity in rodents. Future studies will also explore the applicability of Sendai virus in three-dimensional culture environments, such as organoid cultures, to better mimic the tumor microenvironment.
In conclusion, Dr. Kim and colleagues' study establishes that Sendai virus is a superior gene delivery vector for PDAC derived from human patients, offering new avenues for gene-based therapeutic interventions. This work lays the foundation for future research that harnesses the capabilities of the Sendai virus in clinical and preclinical settings, potentially transforming the landscape of pancreatic cancer treatment.
Magazine reference
Grygoriev D., et al. “Sendai virus is robust and consistent in introducing genes into human pancreatic cancer cells.” Heliyon, 2024.
DOI: https://doi.org/10.1016/j.heliyon.2024.e27221
About the Author
Jungsun KimOf long-standing interest is a reversible regulatory mechanism underlying cancer development and progression, with the ultimate goal of applying the findings in early cancer therapy. To this end, he demonstrated a proof-of-principle PDAC reprogramming model that provides a human cell model for unprecedented experimental access to different stages of human pancreatic cancer. Using this system, they discovered a regulatory network and a secreted or released protein that can discriminate patients with early resectable stage I pancreatic cancer, as well as all stages of PDAC, from healthy controls. Following these studies, Dr. Kim's research will focus on the following areas; “Cancer reprogramming and programming” (1) The role of reprogramming factors in cancer and oncogene-induced barriers in reprogramming (2) Regulatory networks in pluripotency transiently suppress cancer phenotypes (3) The regulatory network during the transition from precursor to invasive pancreatic cancer. He received his bachelor's and Ph.D. in biochemistry from Hanyang University in South Korea under the mentorship of Dr. IL-Yup Chung, and completed postdoctoral studies at the University of Pennsylvania under the mentorship of Dr. Kenneth Zaret.
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