Conditionally replicating adenovirus prevents pluripotent stem cell-derived teratoma by specifically eliminating

Kaoru Mitsui1, Kanako Ide2, Akiko Takayama2

  • 1Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima, Japan ; Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima, Japan.

Insights

Multifactor conditionally replicating adenoviruses (m-CRAs) effectively eliminate undifferentiated human pluripotent stem cells (hPSCs), preventing tumor formation. This discovery offers a novel strategy for enhancing the safety of hPSC-based regenerative medicine therapies.

Area of Science:

  • Regenerative Medicine
  • Oncolytic Virology
  • Stem Cell Biology

Background:

  • Tumorigenicity of human pluripotent stem cells (hPSCs) poses safety risks in regenerative medicine.
  • Anticancer agents, specifically oncolytic viruses, may offer solutions for stem cell safety.

Purpose of the Study:

  • To evaluate the potential of multifactor conditionally replicating adenoviruses (m-CRAs) as antitumorigenic agents in hPSC therapy.
  • To compare the efficacy of survivin-promoter-driven (Surv.m-CRA) versus TERT-promoter-driven (Tert.m-CRA) m-CRAs against hPSCs.

Main Methods:

  • Utilized survivin and TERT promoters to control m-CRA replication in hPSCs and differentiated cells.
  • Assessed viral replication, cytotoxicity, and antitumorigenic effects of m-CRAs in vitro and in vivo (teratoma formation).

Main Results:

  • Survivin promoter showed higher activity in undifferentiated hPSCs than TERT promoter.
  • Surv.m-CRA demonstrated superior killing of undifferentiated hPSCs compared to Tert.m-CRA.
  • Pre-treatment with m-CRAs dose-dependently abolished in vivo teratoma formation from hPSC implantation.

Conclusions:

  • m-CRAs, particularly Surv.m-CRAs, are effective antitumorigenic agents against hPSCs.
  • m-CRAs can significantly mitigate the tumorigenicity risk associated with hPSC-based therapies.
  • This approach holds promise for advancing the clinical application of hPSC-based regenerative medicine.

Related Concept Videos

Teratogenicity01:07

Teratogenicity

The ability of a drug to produce structural deformations and functional abnormalities in the developing embryo or the fetus is called teratogenicity, and the drug producing this effect is known as a teratogen. Teratogenic effects include stillbirth, miscarriage, intrauterine growth restriction, and neurocognitive delay. A teratogen may affect the embryo at different stages of development, which is important in determining the type and extent of the damage. During blastocyst formation, the early...
4.5K
Replicative Cell Senescence02:15

Replicative Cell Senescence

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
4.6K
Rous Sarcoma Virus (RSV) and Cancer01:03

Rous Sarcoma Virus (RSV) and Cancer

Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand  RNA genome. Its genome consists of four main open...
6.6K
In-vitro Mutagenesis01:16

In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
17.7K
Mechanisms of Retrovirus-induced Cancers01:51

Mechanisms of Retrovirus-induced Cancers

Retroviruses are RNA viruses that have been shown to cause cancers in diverse species, including chickens, mice, cats, and monkeys. The RNA genomes of these viruses are first reverse-transcribed into single and then double-stranded DNA (dsDNA) copies. This dsDNA called proviral DNA then integrates into the host genome. Subsequently, the host cell transcribes the proviral DNA in concert with the chromosomal DNA. This leads to the production of viral RNA and proteins that assemble at the host...
7.2K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
6.3K