The History of Gene Therapy
The history of gene therapy was conceptualized in 1972. Gene therapy aka human gene transfer is a field of medicine that aims to treat different diseases by therapeutically delivering nucleic acid into affected cells of patients. Martin Cline was the first person to attempt modifying human DNA in 1980. However, the first successful (and NIS approved) attempt of nuclear gene transfer was performed in 1989. Gene therapy’s scope includes treating diseases at a molecular level by targeting defective genes and correcting what’s wrong with them.
The field is maturing and clinical research is considered to be still in its early stages. Although it’s still being determined for which purposes gene transfer can be useful or its effectiveness, if it works as intended, it could help restore the normal protein functions. It even has the potential of giving existing proteins new functions or improving upon the existing functions of different proteins.
How Gene Therapy Works?
Are you wondering how to start a biotech company? Successful gene transfers involve finding the correct delivery system to carry and deliver the right genes to the affected cells. However, this must be done without causing any damage or adverse effects in the target cells. Delivery also remains the greatest challenge in the field of gene therapy as it’s important to deliver correct genes that would work as intended in the long term.
Researchers often use viruses to deliver correct genes to the affected cells as they have the ability to deposit their own genetic material. The material deposited in the host cells instructs the affected cells to make even more viruses. Viruses’ genetic material contains DNA of the desired gene, but the virus is engineered such that it is not able to reproduce. Researchers are still searching for more effective ways to deliver correct genes to the affected cells using methods other than viruses e.g. liposomes and micropipettes. Read more about the benefits of gene therapy.
The First Gene Therapy Trial
Although gene therapy was conceptualized in 1972, the authors were very cautious about conducting real-world experiments on humans. The first attempt resulted in a failure and was performed on July 10, 1980 by Martin Cline. He even claimed that one of the genes he inserted was active 6 months later, but he did not verified or published his findings.
Research continued on animals throughout 1980s and the first widely accepted gene therapy was performed on September 14, 1990. Early clinical failures resulted in dismissal of gene therapy, but the field regained attention in 2000s and still largely remain an experimental technique. Interested in learning about the future of gene therapy?
Gene Therapy Approaches
Scientists and researchers initially considered two approaches for applying gene therapy to medicine i.e. replacing or disrupting genes that are defective. In the beginning, they focused on different diseases such as hemophilia, cystic fibrosis, thalassemia and muscular dystrophy, which were caused by single-gene defects.
Different techniques were developed to administer DNA, make it reach the damaged cells and replace or disrupt the proteins. One such early technique was incorporating the DNA into a modified virus and delivering it to chromosome. Recent advancements allowed researchers to focus more on direct editing of the DNA using modern techniques such as CRISPR and zinc finger nucleases. Gene therapy can be classified into two categories as follows:
Somatic Cell Gene Therapy
SCGT involves transferring therapeutic genes into cells, but excluding germ cells, gamete, unidentified stem cells and gametocyte. Modifications made using this method only affect individual patients and changes are not passed on to the offspring. More than 600 SCGT clinical trials are underway in the United States alone with most of them focusing on severe genetic disorders such as thalassemia, immunodeficiency and cystic fibrosis (single gene disorders). That’s mainly because the correction or replacement of multiple genes is still uncertain.
Germline Gene Therapy
GTP involves modifying sperm or egg cells (germ cells) by introducing functional genes into gnomes. This causes all cells of an organism to contain the altered gene. This means that the changes are carried over to the offspring and are heritable. Many countries including Canada, Australia, Germany, Netherlands and Switzerland prohibit using germline gene therapy on humans. This is because of its higher risks vs. SCGT, ethical reasons and possible risks to generations to come.
Gene Therapy Timeline
1970s: Friedmann and Roblin proposed in 1972 that good DNA can be used to replace defective DNA (exogenous) in patients who suffer from diseases caused by genetic defects
1980s: The first retrovirus vector system was introduced in 1984 to insert foreign genes into mammals
1990s: The first successful clinical research was conducted on September 14, 1990 at the US NIS (National Institutes of Health). Directed by William French Anderson, Ashanti DeSilva (4-year-old) received the first treatment for a genetic defect.
1992/93: Introduction of cancer gene therapy. First GT using hematopoietic stem cells was performed by Claudio Bordignon at the Vita-Salute San Raffaele University. However, clinical trials were halted temporarily in 2002 when two of the treated children (out of a total of ten) developed a condition resembling leukemia.
2002: Researchers demonstrated that using viral vector can treat sickle-cell disease in mice. Liposomes 25-nm across were also developed, which were able to carry therapeutic DNA.
2003: Two adult patients were treated using gene therapy for chronic granulomatous disease. Researchers also developed a way to prevent the human immune system from rejecting delivered genes by protecting them from being discovered.
2007: First GT trial for retinal disease (inherited) was announced in May
2008: Independent clinical trials were conducted to treat Leber’s congenital amaurosis, Patients recovered without experiencing any side effects.
2010: An adult patient in France successfully gets GT treatment for beta-thalassemia
2011: Neovasculgen registered as the first GT drug in Russia for treating peripheral artery disease
2012: The European Medicines Agency for the first time recommended approval of a GT treatment that compensated for lipoprotein lipase deficiency using Alipogene tiparvovec.
2013: Phase-2 clinical trials started in April at various hospitals to improve heart muscle function and combat heart diseases. Promising results were reported in July, while signs of full recovery were recorded in October (after 18 months).
2014: Clinical trials for sickle-cell disease started
2015: Beta thalassemia treatment clinical trials gain FDA breakthrough-status in February. Scientists from around the world call for a moratorium on editing of inheritable gnome.
2016: Strimvelis GT treatment gets approval of the EMA in June for treating adenosine deaminase deficiency
2017: FDA approves tisagenlecleucel for treating acute lymphoblastic leukemia in August and Luxturna for treating blindness caused by Leber’s congenital amaurosis in December.