SKYSONA™ Gene Therapy for Cerebral Adrenoleukodystrophy

SKYSONA™ (elivaldogene autotemcel) is a gene therapy for boys ages 4 to 17 diagnosed with early X-linked cerebral adrenoleukodystrophy (CALD). The treatment collects and genetically modifies the child’s own cells, which are then given back through a one-time IV infusion. Chemotherapy is first given to make space for the genetically modified cells.

SKYSONA™ was approved by the Food and Drug Administration in 2022. Boston Children’s and Massachusetts General Hospital were instrumental in SKYSONA’s development and approval.

SKYSONA™ is made individually for each child, using a noninfectious viral delivery system, called the lenti-D vector. Lenti-D delivers working copies of the ABCD1 gene, which is mutated in CALD, into the child’s blood stem cells. This healthy gene enables the body to break down very-long-chain fatty acids (VLCFAs) that would otherwise build up in the brain and cause harm. Being able to break down VLCFAs slows the progression of damage to the brain and helps preserve neurologic function.

Boys 4 to 17 years who have the ABCD1 gene mutation are eligible for SKYSONA™ if they have signs suggestive of CALD on brain magnetic resonance imaging (MRI) but have few or no neurologic symptoms.

Our most recent information was published October 2024 in The New England Journal of Medicine. These studies found that after an average of six years of follow up, 81 percent of treated boys were alive and were free of six major functional disabilities, defined as:

• Loss of the ability to communicate
• Blindness
• Need for tube feeding
• Complete incontinence
• Wheelchair dependence
• Complete loss of voluntary movement

SKYSONA™ continues to be studied in a long-term follow-up study. Our hope is that these results will hold up over time and that SKYSONA, if given early enough, will allow children with CALD to live relatively normal lives.

SKYSONA™ treatment does carry risk: It can cause leukemia and another cancerous blood condition called myelodysplastic syndrome (MDS). These potentially life-threatening cancers occur when the lenti-D vector that delivers the ABCD1 gene inserts itself in the wrong place, in or near cancer-causing genes. In the trials published in October 2024, blood cancers, mostly MDS, developed in 10 percent of the children (seven of 67) treated with SKYSONA. 

These cancers developed between one and eight years after gene therapy and were treated with allogenic stem cell transplantation (also called a bone marrow transplant). To date, six of the seven affected children are alive, and four of the seven remain cancer-free. However, one died from graft-versus-host disease, a complication of the stem cell transplant. Two children are still being treated for their cancer.

Because of the cancer risk, our team monitors all children receiving SKYSONA™ with regular blood tests and other assessments for 15 years or longer.

Less serious, more immediate side effects of SKYSONA™ gene therapy may include infections related to the chemotherapy given before the treatment, nausea, vomiting, decreased appetite, constipation, abdominal pain, headache, and rash.

All children are evaluated in our partner Leukodystrophy Clinic at Massachusetts General Hospital (MGH). If they are found to be eligible for SKYSONA, the treatment is managed by the Gene Therapy Program at Boston Children’s. The treatment requires hospitalization for about a month and has several steps.

Boys eligible for SKYSONA™ first receive a four-day course of a medication that stimulates blood stem cells to move from the bone marrow into the bloodstream. A special IV catheter is then inserted to assist with the collection of the stem cells through a collection process called apheresis. The collection requires a two- to three-day stay in the hospital, and more than one session may be required to get enough stem cells.

Next, the stem cells are sent to a manufacturing laboratory where they are treated with the viral vector, a non-infectious virus known as lenti-D. This virus goes into the stem cells and delivers a healthy copy of the ABCD1 gene. After six weeks to three months, the cells are ready to be used for gene therapy and are shipped back to Boston Children’s Hospital.

About 10 days before receiving SKYSONA, children are admitted to Boston Children’s Stem Cell Transplantation Program and receive chemotherapy drugs. These are meant to kill the diseased blood stem cells and make room in their bone marrow for the treated cells.

The chemotherapy can cause nausea, hair loss, vomiting, low blood counts, mouth sores, and fatigue. Because it also increases the risk for infection and can cause organ toxicity, we monitor children closely during this time. Chemotherapy also has potential long-term effects that we will explain to the family.

The treated cells, carrying the healthy ABCD1 gene, are then given back through an intravenous (IV) infusion. The infusion takes about 20 minutes.

Children then remain in the hospital for an average of two to four weeks to allow these new stem cells to engraft, or establish themselves in the bone marrow. Once they do, they begin making cells that have a healthy ABCD1 gene. The cells are now able to break down the very-long-chain fatty acids that cause the serious neurological symptoms of CALD.

After SKYSONA™ treatment

After SKYSONA™ treatment, we will monitor your child closely through visits every three to four months for the first five years, then every six months for an additional 10 years. Initially, these checkups will be at the Boston Children’s Hospital, but may later be available at your home center.

We will be watching for any unwanted side effects from the gene therapy while also monitoring your child’s neurological function and brain MRIs. Contact our team immediately if you see any of these possible warning signs of cancer:

• Abnormal bruising or bleeding, including nosebleeds
• Severe headache
• Unusual stomach or back pain
• Fever (100.4° F or higher)
• Blood in urine, stool, or vomit
• Coughing up blood
• Swollen glands
• Abnormal tiredness

Deciding whether to try SKYSONA™ gene therapy despite the risks can be a difficult choice. We are here to help you navigate this decision.

What we know is that if active CALD is not treated, it is likely to progress rapidly and cause irreversible neurologic decline, which can include loss of communication, blindness, the need for tube feeding, incontinence, wheelchair dependence, loss of voluntary movement, and death, usually within four to eight years.

For some children, allogeneic stem cell transplantation can be an alternative to SKYSONA. Like SKYSONA, it can halt the progression of CALD if done early in the course of disease. The drawback is that it requires a genetically matched donor, which can often be hard to find. Even with a close donor match such as a sibling, stem cell transplants pose a risk of graft-versus-host disease, a life-threatening complication in which the transplanted cells attack the recipient’s body.

Gene therapy with SKYSONA™ does not require a donor because it uses a child’s own cells. However, it poses a risk of blood cancer — a roughly 10 percent risk based on current information. If blood cancer does develop, it would need to be treated with a stem cell transplant from a matched donor, with the hurdles and risks that entails.

Because SKYSONA™ is a new therapy, it may take extra time and effort to get the insurance approvals. Boston Children’s Financial Services staff will provide support and assistance in securing the Insurance authorization.

SKYSONA’s manufacturer, bluebird bio, also offers support with travel, lodging, and other costs associated with treatment relocation.