Nat Biotechnol: Ten years of monitoring have found that AAV, the safest gene therapy vector, has potential carcinogenicity

In recent years, major breakthroughs have been made in gene therapy, and at the end of 2017, Luxturna Therapy, developed by Spark Therapeutics, a well-known gene therapy company, was approved by the FDA of the U.S. Food and Drug Administration, becoming the first "in vivo-given" gene therapy approved in the United States, opening a new chapter in gene therapy.
2019, Novarma's Zolgensma therapy was approved by the FDA to treat spinal muscular dystrophy (SMA), making it the most expensive drug in history, costing $2.1 million, or 15 million yuan, for a one-time treatment.
, however, such sky-high figures make us wonder: How many people can afford treatment, gene therapy is really worth the price? Does it have the effect of "decaying into magic"? Will it have side effects? The journal Nature Biotechnology, a leading international academic journal, published a research paper entitled: A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells.
The study's AAV virus gene therapy trial on dogs with type A haemophilia was effective, and after a decade of observation after treatment, the team found that some of the therapeutic gene fragments carried by the AAV virus were integrated into the dog's chromosomes to control growth, with the possibility of cancer.
this study breaks the myth of the safety of AAV virus vectors and suggests the need for long-term monitoring of the potential genotoxicity of AAV gene therapy.
the study, there were nine dogs treated with AAV with haemophilia A, seven of which successfully stabilized the production of clotting factor VIII.
seems to be exciting news, however, the blood clotting factor VIII. levels in two of the dogs are still rising three years later, and after 7-8 years, they are about four times their initial levels.
further tests found that 1,741 separate AAV integration events were found in the liver tissue of six of the dogs treated, 44 percent of which were near genes involved in cell growth.
addition, some liver cells in five dogs split faster than others and formed subcellular clusters, with amplified cell cloning.
, the team suspects that these integrations activate growth-related genes, causing these liver cells to divide more quickly, which explains why the blood clotting factor VIII. levels in the blood of the two dogs continued to rise.
-related virus, ADENo-associated virus (AAV), is one of the simplest single-stranded DNA defective viruses found.
And recombined adeno-related virus vector (rAAV) originated from non-pathogenic wild adenopathic viruses, with good safety, a wide range of host cells and long expression time in the body and so on, the current scientific consensus is that AAV will not cause any human diseases, so it has become the most promising gene therapy vector.
AAV gene therapy delivers therapeutic genes to specific tissues and organs through the AAV virus, which are stable and expressed in the form of free bodies in these non-divided cells, thus effectively treating single-gene genetic diseases such as haemophilia, familial freezing, etc.
There have been hundreds of clinical trials of gene therapy using recombined AAV vectors worldwide, and two AAV therapies have been approved for market by the FDA.
is a blessing or a curse? In recent years, studies have shown that AVV can insert exogenous gene fragments into chromosomes, which can affect functions such as cell proliferation and apoptosis, and ultimately lead to cancer, which scientists have been worried about.
For the new study, Charles Venditti, a gene therapy researcher at the National Human Genome Institute, said "these new data are both good and bad news" - the integration of genes into chromosomes rather than free state suggests that the treatment will be more durable.
Lillicrap, of Queen's University in Canada, said: "AAV does integrate, but it also makes the effect better and more durable."
we don't know enough about whether this integration of AAV vectors will create cancer risk, " he said.
" In fact, some early gene therapies were based on strategies to integrate therapeutic genes into chromosomes, such as early retroviral therapy, which was so highly vulnerable to cancer.
, AAV viruses are found mainly in non-divided mature cells in the form of free bodies and are considered a safer option.
nearly 20 years, the scientific community's doubts about the safety of AVV gene therapy have never stopped.
previous studies have found that by injecting high doses of AAV virus into newborn mice, it can integrate its genetic material into the DNA of animals, eventually leading to liver cancer.
but many gene therapy experts still believe that the findings in newborn mice are not related to human adults.
but this latest study, conducted in large, adult dogs with type A haemophilia, brings the safety of AAV gene therapy back into the public eye! Scientists have a different view of this.
Even if there is a leak in AAV gene therapy, many researchers believe that integration is relatively low, that the dogs' livers appear to be healthy, do not show signs of tumor or liver abnormalities, and that their coagulation factor VIII. levels are relatively stable.
, however, AAV integration is persistent, in which case it seems only a matter of time before liver cells get new mutations that rapidly divide and multiply and eventually induce tumors.
if these dogs live another five years? Will there be a tumor? Overall, the denise Sabatino team's study in the dog model confirmed that AAV gene therapy integrates gene fragments into host cell chromosomes, especially near genes associated with cell growth, and may cause cancer.
Gene Therapy in 1999, Jesse Gelsinger, an 18-year-old with severe genetic disease paracetamol deficiency, became the first person to die as a result of gene therapy after undergoing a severe immune response following a clinical trial of adenovirus gene therapy led by Professor Jim Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania.
then, the FDA began investigating and rigorously reviewing clinical trials of gene therapy, which resulted in the gradual decline of gene therapy star vector adenovirus, and the entire field of gene therapy began a 20-year silence.
after nearly 20 years of silence, gene therapy, represented by safer AAV virus vectors, has re-emerged.
have been very successful in basic research, clinical trials, and commercialization.
However, just last month, a five-year-old girl with TYPE ADHD (MPS IIIA) died while undergoing a Phase II/III clinical trial of Lysogene's AAV Gene Therapy, becoming the fourth patient to die in a clinical trial of AAV Gene Therapy this year.
Because of the high safety, AAV vector gene therapy developed rapidly and went all the way, but this year four patients died after receiving AAV gene therapy, will this put the brakes on the crazy gene therapy? This Nature Biotechnology paper is a reminder that AAV viruses, which were previously considered very safe, are potentially carcinogenic, so is AAV gene therapy even fatally flawed in the safety of gene therapy? If gene therapy has only one choice in terms of effectiveness and safety, what is the choice? Where will the AAV virus vector go?