Image credit: Texas Children's Hospital
There is a rare class of genetic diseases that make people's immune systems inherently ineffective, and patients can hardly resist any pathogen that invades the body, even pathogens that do not pose a threat to ordinary people may threaten the patient's life. Born in the United States in the 1970s, the "Bubble Boy" unfortunately became one of them, and his tragic experience has also aroused the world's attention to these diseases. Traditional treatments may be expensive, or face long waits or may even end in vain. Recently, recent advances in gene therapy have brought new light to these patients and their families.
In September 1971, a young boy fell to the ground at Texas Children's Hospital in Houston. However, his parents could not caress or kiss the little life, but watched him live in a transparent, sterile plastic bubble. The boy's life seems unavoidable to describe it as "miserable": for the next 12 years, the closed bubble was almost his entire world — he ate, slept, studied, and even baptized in the bubble. The fresh air outside the bubble and the wonderful world are a mortal threat to him.
The boy's name was David Phillip Vetter. Vettel suffers from severe combined immunodeficiency disease (SCID), a collective term for a rare genetic disorder. Patients with SCID are highly susceptible to severe infections due to mutations in genes associated with immune cell development and normal functioning.
The same goes for Vettel, whose immune system is completely unable to function, and any pathogen in the environment could cause him fatal damage. Therefore, immediately after birth, Vettel is placed in a sterile plastic bubble and isolated from the outside world. On weekdays, healthcare workers and relatives must wear gloves to reach Vettel, and everything given to Vettel must be sterilized and sent into the bubble through the airlock. He was also known as the "Bubble Boy".
At the age of 12, Vettel was finally taken out of the bubble, received a bone marrow transplant from his sister, and received a kiss full of maternal love for the first time. But just two weeks later, a dormant virus in his sister's bone marrow revived in Vettel's body and took his tortured life.
"Bubble Boy" Vettel. Image credit: Baylor College of Medicine
But today, some children who suffer from SCID have been able to have a completely different life. Cora Oakley is one of them, and she looks no different from other little girls: healthy, lively, outgoing, loves critters, loves to play with friends.
However, 4 years ago, no one would have imagined that Oakley could have such a carefree childhood: Oakley, who was only 7 days old, was diagnosed with a type of SCID. Fortunately, thanks to the latest medical technology, Oakley does not have to suffer from waiting for a suitable bone marrow match or suffering from immune rejection like other children with this disease.
Oakley, who received gene therapy at 5 months. Image credit: Chelsea Oakley/UCLA Health
<h1 class="pgc-h-arrow-right" data-track="83" > a crippled immune system</h1>
Oakley suffers from severe combined immunodeficiency disease (ADA-SCID) due to adenosine deaminase (ADA) deficiency, one of the more common types of SCID, accounting for about 15% of all SCID cases. The cause is a mutation in the ADA gene, which causes the adenosine deaminase it encodes to function properly. As a result, toxic deoxyadenosine accumulates in cells, preventing lymphocytes responsible for immune function from growing and proliferating normally. The patient's immune function is seriously impaired, unable to resist the invasion of most pathogens such as bacteria, fungi, viruses, etc., and even pathogens that are usually harmless to normal people may pose a fatal threat to patients.
It is estimated that only one in every 200,000 to 1 million newborns has adenosine deaminase deficiency. The main symptoms of the disease include pneumonia, chronic diarrhea, and a widespread rash, which, if left untreated, usually dies within 2 years of age.
For ADA-SCID, the current standard therapy is hematopoietic stem cell transplantation (bone marrow transplantation), in which hematopoietic stem cells from healthy relatives (such as siblings) are transfused into patients. But only about 20 percent of patients can find a successfully matched bone marrow donor, and even if the match is successful, patients who receive bone marrow transplants are still at risk of rejection and graft-versus-host disease.
If a hematopoietic stem cell transplant is not possible, patients can also receive enzyme replacement therapy, in which modified bovine adenosine deaminase is injected into the patient, but this method does not cure the disease, and patients need to be treated frequently (usually every or two weeks). In addition, patients require lifelong antibiotics, antifungals, and monthly immunoglobulin infusions, which are very expensive.
<h1 class="pgc-h-arrow-right" data-track="82" > life-saving virus</h1>
Compared with traditional treatment methods, gene therapy has a wide range of application potential. Previously, studies have carried normal genes with γ-retroviruses as the carrier, introduced into the patient's own hematopoietic stem cells and progenitor cells in vitro, and then transfused back into the patient's body in order to express a normal target product. However, in related clinical trials, some subjects have developed serious side effects such as leukemia and abnormal bone marrow hyperplasia after receiving treatment, which may be due to the carrier incorrectly activating genes that control cell growth.
Compared with γ-retroviral vectors, vectors based on another virus, lentivirus, have higher safety and efficacy. Back in 2008, Donald Kohn of UCLA and Claire Booth of University College London and Great Ormond Street Hospital in London worked with other scientists to develop lentiviral vectors.
Between 2012 and 2017, the cohen and Booth-led research team conducted three Phase I/II clinical trials in the United Kingdom and the United States, using lentiviral vectors and patients' autologous hematopoietic stem cells and progenitor cells to implement gene therapy for 50 infants and children with adenosine deaminase deficiency.
Cohen and lab members. Image credit: Ann Johansson/UCLA Broad Stem Cell Research Center
Recently, the study was published in the New England Journal of Medicine, a top medical research journal. The results of the trial were gratifying: the overall survival rate of patients reached 100%; the researchers followed up on subjects in the United States and the United Kingdom for 2 and 3 years after receiving the therapy, respectively, and the results showed that more than 95% (48) patients could maintain adenosine deaminase in the body at normal levels without receiving either allogeneic hematopoietic stem cell transplantation or continuing to receive enzyme replacement therapy, and toxic metabolites could be metabolized normally; only 2 patients withdrew due to poor efficacy. Enzyme replacement therapy continued and one of them successfully received a hematopoietic stem cell transplant.
Overall, the number of various types of immune cells in the patient's body, including granulocytes, monocytes, lymphocytes, etc., has been restored, and most patients no longer need to receive immunoglobulin replacement therapy by the end of the trial, which means that they have successfully achieved immune reconstruction. In addition, most of the adverse reactions were mild, and no patients experienced autoimmune, graft-versus-host disease, etc., suggesting that the therapy was safe.
It is worth mentioning that 10 patients in the trial conducted in the United States received cryopreserved preparations, that is, doctors can freeze genetically modified hematopoietic stem cells and progenitor cells in vitro and then thaw them before they are imported into the patient's body. This means that gene therapy may become more convenient in the future, and the stem cells needed for treatment can be prepared and transported to the hospital where the patient is located, without the need for the patient to travel long distances to these institutions for treatment.
<h1 class="pgc-h-arrow-right" data-track="53" > the future of gene therapy</h1>
Cohen, who has been working on gene therapies for ADA-SCID and other blood disorders for 35 years, thinks the results of this study are "very encouraging overall." Previously, lentiviral vectors have played a role in gene therapy for genetic disorders such as heterochromatic leukodystrophy (a severe neurodegenerative metabolic disease) and Westcott-Aldridge syndrome (eczema-thrombocytopenia-immunodeficiency syndrome). “
More than 200 patients with various genetic disorders worldwide have received experimental lentiviral gene therapy, and the application of gene therapy to the treatment of ADA-SCID is another major scientific breakthrough. Adrian Thrasher of University College London, Great Ormond Street Hospital in London, was a senior scientist involved in the study and was one of those working with Cohen and Booth to develop lentiviral vectors.
Commenting on the future application prospects of the therapy, Booth said: "If licensed in the future, this therapy may become a standard treatment for ADA-SCID and many other genetic diseases, eliminating the need to find suitable bone marrow transplant donors and not producing the harmful side effects that bone marrow transplants often cause." "Perhaps in the future, more children like Oakley will be lucky enough to escape the clutches of fate, and more families will come out of the haze."
Author: Li Shiyuan
Reviewer: Yang Xinzhou
Thesis Link:
https://www.nejm.org/doi/full/10.1056/NEJMoa2027675?query=featured_home
Reference Links:
https://www.eurekalert.org/pub_releases/2021-05/uoc--gto050721.php
https://www.niaid.nih.gov/news-events/gene-therapy-restores-immune-function-children-rare-immunodeficiency
https://rarediseases.info.nih.gov/diseases/5748/adenosine-deaminase-deficiency
https://medlineplus.gov/genetics/condition/adenosine-deaminase-deficiency/
https://www.ncbi.nlm.nih.gov/books/NBK1483/
https://cn.nytimes.com/lifestyle/20151208/t08retro/