Release date: 2017-11-22

Milan and Elena Villarrea registered Evelyn for a gene therapy trial in which they lost a child because of spinal muscular atrophy. Image source: MIKE SHANAHAN

There was nothing special about the 3-year-old Evelyn with red curls, except that she should not talk to the visitor in the living room at home, wearing a pantyhose followed by a song called "Happy". The song is spinning and dancing.

Evelyn's older sister, Josephine, has a spinal muscular atrophy type I (SMA1) disease, a condition that causes the baby to become paralyzed. Josephine died at the age of 15 months. Evelyn's arrival was an unwanted pregnancy, but her parents still decided to give birth to her, even though the baby had a 1/4 risk of a second tragedy.

When Evelyn was born in December 2014, her parents quickly learned from the genetic test that she also had SMA1. "I know what we have to face, we will always love her," said her father, Milan Villarreal. At 8 weeks, Evelyn received a gene therapy that injected an important missing protein into her body.

Now, she doesn't look too different from any healthy child. In addition to her weak legs and her inability to run or jump, she can still walk very fast, dancing, drawing letters, throwing foam blocks, moving small chairs, or climbing to the legs of her mother, Elena. The Villarreals family has seen Evelyn go from crawling to walking to speak. "It's like a miracle. Every journey is like a celebration. We will celebrate the champagne for every little thing she does," Milan said.

The results of clinical trials involving Evelyn have also shocked many gene therapy researchers, making it the most visible success in this once-popular field. A total of 15 babies were treated with SMA1, otherwise they would die when they were about two years old. According to a recent report published in the New England Journal of Medicine (NEJM), these babies have now grown to 20 months or more, and most of them have already sat. This gene therapy is a one-time treatment that works by simply injecting it into the vein. "I have never seen the effect of any gene therapy on the deadly disease," said Jerry Mendell, a neuroscientist at the National Children's Hospital in Columbus, who led the recent trial.

This news adds momentum to gene therapy. A treatment for blindness by gene therapy was approved by the US Food and Drug Administration (FDA) panel in October this year, and the therapy will be the first gene therapy approved in the United States for the treatment of hereditary diseases. In addition, the safety and success of this new treatment is motivating other researchers to use gene therapy for intravenous or spinal injections to treat rare childhood neurological or muscular diseases, even for treating adult diseases such as Parkinson's disease.

Isolated viral vector

Initially, when a patient is an animal, it seems easy to treat a neurological disease with gene therapy. In the 1990s, researchers injected viral vectors carrying missing genes into the brains of new-born mice that were genetically engineered to have specific metabolic diseases. Mark Sands of the University of Washington School of Medicine in St. Louis, Missouri, said the results were "shocking and the results were so good." But he added that the mouse brain is small. “The challenge is how to extend from a mouse brain that weighs only half a gram to a child's brain with a mass of 1000 grams. This is a 2000-fold difference in size. How do you get it to work?”

The results show that it is difficult for researchers to do this. In 1996, a team injected fat particles containing a therapeutic gene into the cranial cavity of two children (a brain disease known as Kanawan disease). The study was highly controversial and did not help patients. Subsequently, the same group of researchers drilled 6 holes in the skull of another 13 patients with Kanawan disease, and injected a vector formed by a clearly harmless virus, adeno-associated virus (AAV), for treatment; The AAV trial was also used to treat Bedton's disease with a serious childhood hereditary encephalopathy.

However, no treatment has alleviated the disease. A completely different treatment method produced the only successful treatment of a neurological disease. After the researchers extracted the hematopoietic stem cells from the patient, they were sutured into a new gene using modified HIV (HIV) and the cells were reinfused into the patient. Some of these cells migrate to the brain and then form a nerve-supporting cell called glial (which produces the desired protein). According to an article published in NEJM in October this year, this “in vitro” gene therapy prevented a deadly disease called adrenal white matter dystrophy (ALD) among 15 boys. Will destroy the myelin sheath around the neurons. Italian gene therapy researchers have reported similar treatments for young patients with metachromatic leukodystrophy encephalopathy.

However, ex vivo gene therapy is most effective for brain diseases caused by the lack of secreted proteins: transplanted cells can replace it by generating molecules for other nerve cells. For many disorders, the missing protein is run inside the cell, so all cells that need it must receive the vector.

From death to hope

The viral vector that responded to this demand began with a death case. At the beginning of the 21st century, one of the leaders in the field, Pennsylvania State University geneticist James Wilson was asked to change the direction of research. In a clinical trial led by Wilson in 1999, 18-year-old Jesse Gelsinger died of a large-scale response to a potent adenoviral vector, which he received for the treatment of liver disease. Wilson had an economic interest in the trial, and he faced a litigation by the Gelsinger family and a FDA investigation, and he eventually accepted a five-year ban on these leading clinical trials. He then turned to finding new AAVs, which are safer than adenoviruses and have become a popular carrier.

In 2004, Guangping Gao of the Wilson Laboratory reported that they combed human and primate tissues and found more than 100 new AAVs with "trends" or priorities that could be used to infect certain types of cells. One of them, AAV9, is "different from any other AAV. Wilson recalls that when it is injected into the blood at high doses, it will reach everywhere" - heart, muscle, brain tissue. The most attractive is that it directs the ability of the target to track neurons, which are the key to many brain and spinal cord diseases.

Other researchers are scrambling to confirm the effects of AAV9 on the nervous system. In 2009, a French team and the National Children's Hospital Brian Kaspar's lab published papers to promote research in this area. The babies born after SMA1 are soft and cannot suck or look up very well; because of the loss of spinal motor neurons, their muscles will weaken and they will not breathe at a certain moment and will die. The team led by Kaspar set out to study a method of genetically editing AAV9 to carry the SMN gene.

Newborn mice with SMA1 in their presence have normal motor function and life cycle after this therapy, and they plan to have an intravenous injection. Monkey tests have shown that the relevant dose is safe. The FDA and the Restructuring DNA Advisory Board (the National Institutes of Health review of most US gene therapy trials) approved the study, and the National Children's Hospital and a foundation funded it.

Shortly after the first infant received the AAV9 therapy test dose, her liver enzymes rose to 31 times normal, suggesting that cell damage may occur. "I couldn't sleep that night," Mendell said. But steroids quickly lowered liver enzyme levels, and the FDA advised him to continue. The other three infants also had elevated liver enzyme levels, but there were no clinical signs of liver damage, so the trial continued.

Although the purpose of the trial was primarily to test the safety of the therapy, it quickly became clear that the introduced gene slowed the baby's atrophy. The baby does not become softer and harder to breathe, but becomes stronger. Evelyn's belly was posted on the floor and one day began to look up, recalling Elena Villarreal. "It's like something that can never happen after suffering from SMA1." Now, of the 15 treated babies, only 8 need a mask to help with breathing.

Exciting expectations

It is still unclear how long this treatment will work. Unlike HIV and other viruses used for ex vivo gene therapy, AAVs do not integrate therapeutic genes into the genome of cells; they store them as a free-moving DNA cycle, which means that when cells replicate themselves, These effects will disappear. But Kevin Flanigan, director of the National Children's Hospital Gene Therapy Center, says neurons don't divide, so treated tissues should continue to produce SMN proteins for years.

If the benefits of this gene therapy eventually resolve, SMA1 patients will need to be retreated, but by then they already have AAV9 antibodies in their bodies that may block it. But Mendell said researchers at the National Children's Hospital are investigating countermeasures, such as filtering antibodies from the blood or providing specific immunosuppressive drugs.

Another worry that is a little further away is cancer. Studies conducted by Sands and others have found that when large doses of rats are injected, some AAVs pass their DNA into the genome, leading to liver cancer. Sands pointed out that scientists still don't know whether those results will be related to humans. Some gene therapists are convinced that in past gene therapy trials, liver cancer did not appear in thousands of patients.

AveXis has launched another SMA1 study that plans to treat the milder symptoms of the condition. Now, high-dose, systematically imported AAV gene therapy seems to be safe, and the National Children's Hospital and other agencies are launching clinical trials for other neuromuscular diseases that aim to import new genes into muscle cells rather than neurons.

Early treatment is critical for patients with SMA1 and other progressive diseases. "Once the neurons disappear, they disappear forever," said Jonathan Mink, a pediatric neurologist at the University of Rochester Medical Center in New York.

Some researchers are still skeptical about this less invasive delivery of AAV9 to new methods of reaching enough brain cells. Other gene therapy experts hope to find new AAV vectors that can even better cross the blood-brain barrier.

The SMA1 study allowed Evelyn's parents to have a little girl who can dance, because the gene therapy experts excited by this study are eager to see if there is a similar strategy to save more children with severe genetic diseases. If so, the status of gene therapy in medical "Arsenal" will be affirmed. Wilson said: "This is not a minor improvement. It is a revolutionary change that we have always hoped for gene therapy."

Source: Science Network

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