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Help finding self-replicating moveable genetic elements specific for cancerous cells

Image credit: Photo Credit: Cynthia Goldsmith Content Providers(s): CDC/ Dr. Terrence Tumpey/ Cynthia Goldsmith - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #8243.

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mschiav3
mschiav3 Apr 11, 2022
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I am looking for a way to spread a gene, specifically between cancerous cells, it needs to be self-replicating, like a lentivirus or something like that, that can modify specifically cancerous cells and spread through cancerous cells populations, do not need to spread quicklly, just be able to reach surrounding cells and metastatic cells in any organ.
I have done some search on NCBI and other platforms, however I could not find something to that level of specificity.
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Use oncotropic viruses

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Subash Chapagain
Subash Chapagain Apr 11, 2022
The first go-to approach would be to use engineered Oncotropic (or oncolytic) viruses (OVs) for tumour targeting.
Naturally, oncolytic viruses are selective for tumours. OVs like bovine Herpes simplex virus -1 (HSV-1), reovirus, parvovirus, and vesicular stomatitis virus (VSV) have an inherent capacity for oncotropism, i.e selective infection of cancerous cells. Both DNA and RNA viruses with oncolytic abilities have been identified, and the choice of which one to use completely depends on our end goal. If we want high genome stability and replication, oncolytic DNA viruses are suggested. However, if the goal is to induce a more immunogenic response, oncolytic RNA viruses are better candidates.
OVs engineering to specifically target cancer cells and not normal cells a) The best way to use an engineered OV would be to engineer it to target tumor cells and tumor-associated stromal elements, while detargeting normal, non-tumor cells. Complex mosaic systems designed by modifying adenovirus vectors to contain hybrid fibers has been shown to target tumor cell population. In vivo, when the fiber modification was supplemented with pan-cancer ligand, specific targeting was attained in different cancer cells .
b) Another trick for selective targeting is to inhibit replication of the virus in normal cells by deleting genes that are functionally active in normal but defective in cancer cells (genes in tumor suppressor pathway). This makes it possible for the virus to replicate only in tumor cells. In fact, this is the mechanism used by T-VEC, the only approved OV based cancer treatment to date. T-VEC contains an HSV-1 backbone in which RL1, the gene encoding cell protein ICP34.5, is deleted. The protein ICP34.5 is a rescue mechanism for viral replication in normal cells where interferon responses inhibit viral replication. However, since tumor cells lack efficient interferon responses, the deletion of 34.5 gene effectively rescues the virus and it can easily replicate in the cancerous cells .
c) Substituting/inserting proteins from other viruses for tumour targeting. In one study, the researchers engineered a chimeric VSV that lacks its natural neurotoxicity yet retains the potent oncolytic activity. The envelope glycoprotein G of VSV was replaced with another glycoprotein of lumphocytic choriomeningitis virus (LCMV). This modified virus was found to effectively eliminate brain cancer while remaining benign in the normal brain, as seen in preclinical in vivo models .
Similarly, when thymidine kinase (TK) gene in HSV-1 was modified in HSV-1 and VACV, it allowed for selective replication in cancer cells .
Given we have correctly engineered the OV, how do we ensure it spreads efficiently? For tumour-targeted viral infection, the spread of the virus needs to be efficient. Generally, extracellular matrix (ECM) that is composed of hyaluronic acid and collagen serves as a physical barrier that can prevent the engineered virus from penetrating and spreading within the tumor tissue. To overcome this stromal barrier, different strategies have been suggested. For instance, ECM-degrading protein like relaxin can be used. Oncolytic adenovirus with relaxin expression degraded fibrotic ECM in pancreatic cancer and enhanced tumor penentration .
Another protein that can be used to degrade ECM components is decorin, a proteoglycan. Decorin expressing adenovirus was found to enhance tissue penetration. Decorin acts via different mechanisms: by decreasing collagen fibril diameter, by inhibiting transforming growth factor-beta (TGF-B), and by promoting matrix metalloproteinase-1 activity. For solid tumours, the protein VCN-01 has shown improved targeting and efficacy.

[1]https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095723

[2]https://ascopubs.org/doi/10.1200/JCO.2014.58.3377?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

[3]https://pubmed.ncbi.nlm.nih.gov/24812275/

[4]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582515/

[5]https://pubmed.ncbi.nlm.nih.gov/28315430/

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mschiav3
mschiav32 months ago
Wow, great Subash. I can see you reported the OVs, however, I was wondering if there is a way for the Oncolytic virus not to be lytic and find a way to make it behave like inoviridae phages behave in bacteria (a virus that multiplies and does not lyse the cell when it is spreading, or that do not kill the cell). Maybe an OV that is not multiplying heavily and that can homeostatically survive and multiply among the cancerous cells.
Your insights were very helpful.
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Subash Chapagain
Subash Chapagain2 months ago
mschiav3 Thanks. I have proposed another solution in the next contribution, please see if it makes sense to use exosomes as vehicles to spread your gene of interest.
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Use engineered extracellular vesicles to distribute your gene of interest

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Subash Chapagain
Subash Chapagain Apr 11, 2022
Extracellular vesicles are nanoscale lipid membrane-bound particles released by cells as communicative vehicles that deliver messages throughout the system. Exosomes are a type of extracellular vesicles with a size range of 30-150 nm. Exosomes can transfer protein, nucleic acids and lipid cargo between cells upon their secretion. The cargo carried by these exosomes can be used to induce various signalling pathways in the recipient cells. Exosomes can be the best candidate for proposed gene spread/delivery because a) they are able to transfer a variety of biological cargo
b) they do not induce immunogenicity and toxicity, they are highly biocompatible
Either genetic or chemical modification of extracellular vehicles can be used to make them more specific and selective in the target. Donor cells (cells used to produce EVs) can be engineered to produce EVs with modified receptors to increase cellular recognition. For example, surface proteins such as LAMP2b and tetraspanins can be expressed in the EVs, fused with ligands or targeting signals. Functional proteins can be displayed on the EV surface. Such functional displaying has been used in case of dendritic cells (DCs). DCs engineered to produce exosomes with LAMP2b and iRGD integrin specific peptides enhanced the efficiency of drug delivery to alpha-gamma positve breast cancer in mice models .
Similar system can be exploited to deliver the target gene to the tumor population that specifically expresses a tumor-associated marker. Successful neuronal delivery of engineered exosomes has been proven in treatment of brain cancer in zebrafish as well .

[1]https://pubmed.ncbi.nlm.nih.gov/24345736/

[2]https://www.nature.com/articles/s41551-019-0485-1

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Contrived _voice
Contrived _voice2 months ago
I was thinking along this line but with something else. I found this article on using RNA sequencing to detect mutations. . Could it be possible to engineer a comparative RNA polymerase transported via extracellular vesicles that once inside a cell scans for specific dominant mutations and once it finds them adds a sequence on the m-RNA that forces the affected cell to destroy itself?

[1]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694122/

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Subash Chapagain
Subash Chapagain2 months ago
Contrived _voice Using RNA seq analysis to detect mutations, especially single nucleotide polymorphisms (SNPs) is a routine method used in molecular biology, and it might be useful. However, to engineer an RNA polymerase with a proofreading mechanism might be really difficult if not impossible. Such a scanning and correcting mechanism is the intrinsic property of DNA polymerases but I am not sure if RNA polymerases do that. It would be a marvel if we could engineer an RNA polymerase to have such proofreading capacity. Another alternative approach would be to arm the exosomes with pattern recognizing proteins that can specifically bind to tumors, and engineer them such that upon binding with the tumor, they activate tumor-degrading signals (perforins and granzymes for example) that kills the tumor.
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mschiav3
mschiav32 months ago
That is more like it. I guess matching both the replicative property of OVs and the spread method of EVs will be a great way to solve that issue. I have another challenge I am working on right now, that is more elusive to solve than this one. I am looking for something (a peptide probably) that can work between cancerous cells as bacteriocins work between bacterial cells. I shall create that challenge.
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