By Dr. Liji Thomas, MD Jan 8 2020
A recent report on the results of a 10-year gene therapy study in dogs, which was presented on December 9, 2019, at the American Society of Hematology (ASH) meeting in Orlando, Florida, has stirred up old fears that by using a virus to insert therapeutic genes into the human genome, scientists may inadvertently be pushing cancer buttons in the treated cells. Image Credit: Kateryna Kon / Shutterstock.com
Gene therapy has always been the Holy Grail of medicine when it comes to conditions that are caused by defective genes. Recently, the use of a harmless virus called adeno-associated virus (AAV), which is capable of infecting human cells without any apparent ill-effects, has made it easier to introduce targeted sequences of corrective DNA into a defective cell to repair a gene.
The inserted DNA formed a loop called an episome that floated free within the nucleus rather than becoming a structural part of the host chromosome. Why AAV is required
For gene therapy, the replacement gene needs to be injected into the target cell so it can become part of its genetic database. Early experiments on gene therapy used a viral vector; it infected the target cell and thus inserted the whole of its genome into the host cell chromosomes. However, when this was found to have induced tumors in some children, this approach was halted.
This is why the AAV appealed to genetic researchers, and this vector has been behind many novel gene therapies introduced recently. For instance, in 2019, the U.S. Food and Drug Administration approved a gene therapy for spinal muscular atrophy, a hereditary neurological condition that eventually kills the individual.
Another such therapy is designed to treat hemophilia B in which the person has a gene defect that prevents the production of an essential clotting factor. This therapy aims to insert a therapeutic gene into the liver by means of doctored-AAV infection of liver cells, making the liver capable of producing the missing protein. It is slotted for approval in 2020.
Currently, target genes are often injected into a modified version of the AAV, which is used as a ferry or a vector to get the gene into the cell in a way that will ensure it remains intact. The use of the AAV was justified by previous observations that it hardly ever incorporates its own genome into the host chromosomes, minimizing the risk that it could introduce cancer-causing mutations. The new study shows that this might indeed happen. The study
The study involved nine dogs with hemophilia A, caused by the genetic deficiency of the crucial clotting factor called Factor VIII, which was treated by gene therapy. The AAV virus inserted the therapeutic gene successfully. The dogs were sacrificed once the experiment ended after a follow up of up to 10 years, and 6 of the livers were examined. The findings
Seven of the nine dogs that had received the replacement gene showed a stable increase in the level of Factor VIII in 7 of the animals. In the other two dogs, the increase continued to occur after a period of about three years, and eventually, these dogs had a fourfold rise in Factor VIII by the end of 7-8 years.
The scientists found that in all 6 of the livers examined after the experiment ended, the DNA introduced by the AAV vector had inserted itself into the dog’s genome at multiple loci. In some cases, it was the Factor VIII gene, but in many more, it was a part of a regulatory sequence that was incorporated in spotty fashion across the dog chromosomes. With some of these, the regulatory fragments were perilously located near genes that control cell growth. Related Stories
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