IT and IV Lentiviral Gene Therapy for X-ALD

X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1). ABCD1 is responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. X-ALD is clinically characterized with two main phenotypes: adrenomyeloneuropathy (AMN) and the inflammatory cerebral ALD. This disease presents most commonly in males. Approximately 50% of heterozygote females show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. The disease is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. ALD patients are normally treated with hematopoietic stem cell transplantation (HSCT) from a matched healthy donor. However, HSCT must be performed at a very early stage of the disease, which limits the therapeutic opportunities for juvenile or adult forms of ALD. This trial aims to treat ALD using a safety and efficiency improved self-inactivating lentiviral vector carrying a functional ABCD1 gene via intrathecal (IT) and intravenous (IV) injections to directly correct the genetic defect. This protocol targets not only early stage patients but also patients with symptoms. The direct LV injection approach aims to correct the pathologies associated with this genetic defect, and the IT and IV LV injections substantially simplify the treatment process, which reduces the risk associated with myeloablative chemotherapy during the HSCT treatment.

The objectives are to evaluate the safety of the advanced self-inactivating LV TYF-ABCD1, the direct in vivo gene transfer clinical protocol and the efficacy of the treatment, including assessment of vector distribution and the potential long-term correction of the ALD disease phenotype.

Inclusion criteria

• X-ALD patients ≥ 1 year of age
• ALD diagnosis of the brain: evaluation of the VLCFA value in plasma
• Central imaging of the MRI to examine the damage on the CNS.
• Neurological function score (NFS) ≥ 1
• Parent / guardian / patient signing informed consent
• Patients and their families have a strong willingness to participate in clinical trials, and are willing to bear all the consequences caused by the failure of the trial, and sign an informed consent form

Exclusion criteria

• HIV positive patients
• Stablized condition after statins, Lorenzo's oil, or diet to reduce VLCFA levels
• Patients who are experiencing severe viral, bacterial or fungal infections, malignant tumors, heart abnormalities, liver dysfunction, or renal insufficiency
• Cannot perform an MRI
• Infection or dermatosis at pre-injection site