Final Steps And Concluding Statements

Hello! Today, we will discuss essential parts of the discussion section I completed as part of my research. Specifically, we will dive into the limitations of the gene treatment, how the gene treatment is an improvement from current treatment methods, and the future directions for my research. I have finished writing my paper, and I have submitted it for publication to JEI this week.  

Current Treatment Methods 

The suggested genetic treatment has the potential to significantly alter how HNPCC is managed.  To avoid the onset of colorectal cancer, individuals with HNPCC are currently advised to have a complete colectomy at age 20.  The procedure is extremely invasive and can be associated with numerous post-operative morbidities, including bleeding, infection, surgical adhesions, etc.  Most significantly, this procedure makes patients reliant on parenteral (intravenous) nutrition for the remainder of their lives from a young age. By reinstating the DNA mismatch repair mechanism in colonic crypt cells (which is causally connected to colorectal oncogenesis in HNPCC), the suggested genetic treatment may be able to prevent the need for a colectomy. The effectiveness of this genetic treatment in preventing carcinogenesis will be determined by longer-term investigations using animal models of colon cancer in Lynch syndrome. 

Limitations 

It is important to note that the suggested genetic treatment has certain limitations. It is not advisable for individuals with HNPCC who have mutations in other domains of MLH1 and MSH2 or other MMR proteins, as it can only be helpful for those with mutations in the specific foci targeted by our gRNA. Nonetheless, the pipeline outlined in this work can be used to customize the general approach to specific patients. However, there are some issues to consider, such as the need to deliver multiple plasmids to target cells using IDLVs, which may affect the packaging effectiveness. Additionally, substantial doses of IDLVs may be necessary for therapeutic effectiveness. It remains to be determined whether administering IDLVs or another viral vector with an affinity for colorectal crypt cells through intrarectal delivery would allow for the targeted treatment of lower dosages. Furthermore, IDLVs have never been tested in clinical trials for genetic therapy, so it is vital to clarify the safety of using extremely high dosages. 

Future Directions 

In conclusion, this research supports the adoption of personalized medicine. While the current treatment focuses on specific regions in two genes, it can target any region within those genes if the gRNAs adhere to the rigorous checkpoints outlined in this study. This non-invasive approach tackles the underlying biological and molecular causes contributing to Lynch syndrome, as opposed to the conventional standard of care. If pre-clinical trials prove successful, there is a potential opportunity to conduct clinical trials in the future to evaluate the effectiveness of targeted genetic therapies in enhancing patient outcomes and prolonging survival.