How Adrenoleukodystrophy Gene Therapy Treats ALD

Adrenoleukodystrophy (ALD) is a rare genetic disease affecting the nervous system and adrenal glands. As an X-linked disorder, it is caused by a mutation on the X chromosome, resulting in males experiencing more severe symptoms. The condition arises from mutations in the ABCD1 gene, which is responsible for creating a protein that breaks down very long-chain fatty acids (VLCFAs).

When the ABCD1 gene is faulty, VLCFAs are not properly processed and accumulate to toxic levels. This buildup is particularly damaging to the adrenal glands and the myelin sheath, the protective coating that insulates nerve cells. The destruction of myelin, called demyelination, disrupts the nerves’ ability to communicate with the brain.

The most severe form is cerebral ALD (CALD), which typically appears in young boys between four and ten and is characterized by rapid neurological deterioration, leading to severe disabilities if not addressed.

The Scientific Basis of Gene Therapy for ALD

The gene therapy for ALD is an ex-vivo treatment, where a patient’s cells are collected and modified in a laboratory before being returned to the body. This approach uses the patient’s own hematopoietic stem cells (HSCs), which are blood-forming stem cells, as a vehicle for delivering a corrected gene.

To deliver the functional gene, scientists use a lentiviral vector. This vector is derived from a virus that has been disabled to make it safe for clinical use and is engineered to carry a healthy copy of the ABCD1 gene. During the laboratory phase, this lentiviral vector is used to transduce, or infect, the patient’s collected HSCs.

The vector inserts the functional copy of the ABCD1 gene into the DNA of the stem cells, correcting the genetic defect. Once these genetically modified HSCs are infused back into the patient, they engraft in the bone marrow and begin producing new, healthy blood cells. These new cells can produce the functional ALD protein, allowing the body to properly break down VLCFAs and halt the inflammatory process that destroys myelin.

The Patient Treatment Journey

The first clinical step is collecting the patient’s hematopoietic stem cells. The patient receives medications, such as Granulocyte-Colony Stimulating Factor (G-CSF), that encourage stem cells to move from the bone marrow into the circulating bloodstream, a process called mobilization. They are then collected through apheresis, where blood is drawn, filtered by a machine to separate the stem cells, and returned to the body.

After collection, the harvested stem cells are sent to a manufacturing facility where they are exposed to the lentiviral vector carrying the functional ABCD1 gene. This manufacturing and testing process can take 51 to 65 days before the modified cells are shipped back to the treatment center.

While the cells are being modified, the patient undergoes a preparatory regimen called conditioning. This involves receiving myeloablative chemotherapy to clear out existing, unmodified stem cells from the bone marrow, which “makes space” for the new, gene-corrected cells to establish themselves.

Once conditioning is complete and the modified cells have arrived, they are infused back into the patient’s bloodstream through a central venous catheter. This procedure is similar to a standard blood transfusion. Following the infusion, the patient remains in the hospital for approximately two months for close monitoring as the new cells engraft.

Therapeutic Outcomes and Efficacy

The primary therapeutic goal of this gene therapy is to stop the progression of neurological symptoms in boys in the early stages of cerebral ALD. Success is not measured by reversing damage that has already occurred, but by preventing further decline. The main metric used to assess effectiveness is “Major Functional Disability-free survival,” which tracks whether patients remain alive and avoid the onset of severe, irreversible neurological impairments.

Major Functional Disabilities (MFDs) are a set of six specific, life-altering conditions:

• The loss of the ability to communicate
• Cortical blindness
• The need for a feeding tube for nutrition
• Total incontinence
• Dependence on a wheelchair for mobility
• The complete loss of voluntary movement

The onset of any one of these disabilities marks a significant progression of the disease. Clinical trials, such as the Phase 2/3 Starbeam study, have provided data on this treatment. In this study, 88% of participants who reached the two-year post-treatment mark were alive and free of major functional disabilities. Data from a cohort of 32 patients showed that at a median follow-up of over three years, 90.6% met the primary endpoint of MFD-free survival at 24 months, indicating the treatment stabilized neurological function in most patients.

Eligibility and Potential Complications

Eligibility for ALD gene therapy is highly specific and is not an option for all patients. The treatment is approved for boys between 4 and 17 who have been diagnosed with early, active cerebral ALD. An “early” diagnosis means that brain imaging shows evidence of demyelinating lesions, but the patient has not yet developed severe neurological symptoms. Candidates have a neurologic function score (NFS) of one or less, indicating mild or no functional impairment.

The therapy is not intended for those with advanced disease or for individuals with the adrenal-only form of ALD. The treatment process carries risks, many of which are associated with the required conditioning chemotherapy. The myeloablative drugs used to clear the bone marrow can cause significant side effects, including:

• Nausea
• Vomiting
• Hair loss
• An increased risk of serious infections

These complications are managed in the hospital setting during the recovery period. A more serious risk is insertional oncogenesis, the potential for the lentiviral vector to cause cancer. The vector inserts the ABCD1 gene into the patient’s DNA, and if this insertion occurs near a gene that regulates cell growth (an oncogene), it can inadvertently activate it, leading to uncontrolled cell proliferation.

This has been observed in clinical trials, where a number of patients developed myelodysplastic syndrome (MDS), a type of blood cancer. This risk, which has been estimated at around 10%, is a significant concern that must be weighed against the benefits of halting ALD progression. Patients who develop this complication may require additional treatments, such as a stem cell transplant from a donor.