▌ Story: Gene therapy that changes a child's life
In April 2017, a seven-day-old girl, Cora Oakley, was genetically screened for adenosine deaminase deficiency (ADA-SCID) in newborns.
This is a rare genetic disease in which the child is severely immunodeficient due to the inability to produce ADA enzymes in the body and can even live only in a sterile "bubble".
The more famous "Bubble Boy" is David Philip Witt, who has lived in a sterile transparent plastic isolation cover since birth. In February 1984, after 12 and a half years of struggling with illness and loneliness, David eventually died.
Fortunately, Cora became the last participant in a gene therapy clinical trial 3 months after his diagnosis. Today, Cora is 4 years old and has grown into a healthy, lively child. Cora's parents said: "Gene therapy has done wonders and changed the life of their daughter. ”
Recently, this research gene therapy OTL-101 has been effective in clinical trials for the treatment of patients with adenosine deaminase deficiency.
The results of the trial showed that the overall survival rate of patients after receiving a gene therapy treatment was 100% at 2 or 3 years, and more than 95% of patients had significant improvement in immune system problems, and no other therapy was needed to control the disease.
▌ "Bubble Boy", may not wait for hematopoietic stem cell transplantation for life
Adenosine deaminase deficiency (ADA-SCID) is a rare, life-threatening inherited immunodeficiency caused by a mutation in the ADA gene. The gene encodes the production of adenosine deaminase, which is essential for the functioning of the immune system.
Due to the loss of adenosine deaminase, cells such as B cells, T cells, and natural killer cells in the patient's immune system are dysfunctional. As a result, patients with ADA-SCID have almost complete loss of resistance to viruses, bacteria, and molds, and need to live in a sterile environment for a long time.
ADA-SCID usually develops symptoms of infection in infancy and, if left untreated, generally does not live to be 2 years of age.
Currently, the most important and effective treatment options for the disease are enzyme replacement therapy and hematopoietic stem cell transplantation. For hematopoietic stem cell transplantation, it is not easy to find a donor that matches the patient. "Bubble Boy" David waited for more than a decade and ultimately failed to wait for a suitable donor.
Then, in June 2016, stem cell gene therapy Strimvelis was approved by the European Union for the treatment of ADA-SCID. This is the world's first corrective gene therapy approved to treat ADA-SCID without the need for matched stem cell donors, avoiding the risk of graft-versus-host disease.
Strimvelis gene therapy is the use of a virus to replace the missing genes in the bone marrow of children with ADA-SCID. The researchers took stem cells from the patient's bone marrow, then introduced a normal copy of the ADA gene into it, and finally re-infused it into the patient's body, allowing the patient to regain the production of ADA enzymes and thus restore immunity.
▌ Lentiviral gene therapy, safer and more effective!
Normally, gene therapy uses viral vectors made of retroviruses, which limit the potential for treatment because viral vectors can only enter the nucleus to deliver genes when cells divide, limiting the number of cells receiving gene payloads. Moreover, it is very likely to cause some serious side effects, such as leukemia.
However, modified lentiviral vectors can enter the nuclei of non-dividing cells, making gene therapy safer and more effective.
OTL-101 is an autologous hematopoietic stem cell gene therapy. The researchers isolated hematopoietic stem cells from the patient's body and reintroduced the "modified" ADA gene into the patient in vitro through a modified lentiviral vector.
These engineered hematopoietic stem cells are able to proliferate and differentiate in the patient's body, recode adenosine deaminase, and continuously produce healthy immune cells to fight infection.
Previously, OTL-101 has been granted orphan drug status, breakthrough therapy designation, and rare pediatric disease certification by the U.S. FDA for the treatment of ADA-SCID.
▌ The total survival rate is 100%, and the new dawn for children with rare diseases!
This positive data comes from the findings of three Phase 1/2 clinical trials. Two of them were conducted in the United States and one in the United Kingdom. A total of 50 patients with ADA-SCID received gene therapy, 30 in the United States and 20 in the United Kingdom.
The results, published in the New England Journal of Medicine, show that:
· At the end of the follow-up, the overall survival rate of ADA-SCID patients receiving gene therapy reached 100% (2 years in the US and 3 years in the UK). Moreover, more than 95% of patients had significant improvements in immune system problems.
· After one year of treatment, the event-free survival rate (meaning that patients do not need other means to control the disease) is 97% in the United States and 100% in the United Kingdom.
· After 2 years of treatment, the event-free survival rate of patients in the United States remained at 97%, compared with 95% in patients in the United Kingdom at 2 and 3 years. Overall, gene therapy is safe.
Currently, more than 200 patients with immunodeficient diseases worldwide are being treated with experimental lentiviral gene therapies, including ADA-SCID.
Patients with ADA-SCID face the dilemma of injecting ADA enzyme replacement therapy multiple times a week or without a suitable donor, and are expensive. This improved version of lentiviral gene therapy has shown long-term and sustained efficacy in the treatment of ADA-SCID.
Once approved, the gene therapy could become the standard of treatment for ADA-SCID and other genetic disorders, reducing the need to find a matching donor for bone marrow transplantation and greatly reducing the toxic side effects associated with clinical treatment.
Resources:
https://bionewscentral.com/gene-therapy-offers-potential-cure-to-children-born-without-an-immune-system/
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