Elivaldogene autotemcel (Skysona)

概览

Elivaldogene autotemcel is a gene replacement therapy for treating early cerebral adrenoleukodystrophy comprising autologous hematopoietic stem cells transduced with a viral vector encoding ABCD1 complementary DNA for human adrenoleukodystrophy protein.

作用机制

Adrenoleukodystrophy protein (ALDP or ABCD1) is a half ATP-binding cassette (ABC) transporter localized in the peroxisomal membrane. It plays a role in peroxisomal beta-oxidation and the breakdown of very long-chain fatty acids (VLCFAs) in organs. Adrenoleukodystrophy is an X-linked genetic disorder caused by the mutations in the ABCD1 gene that encodes ALDP, leading to impaired production of ALDP. The lack of functional ALDP leads to increased intracellular concentrations of VLCFAs and incorporation of VLCFAs into different complex lipids, including myelin sheaths that are particularly vulnerable to inflammation. VLCFA-induced myelin membrane instability leads to a pro-inflammatory brain environment, causing progressive, inflammatory cerebral demyelination and axonopathy. These pathological events can also be accompanied by oxidative stress and energy shortage in axons as well as non-cell-autonomous processes involving axon–glial interactions. Elivaldogene autotemcel consists of autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding ABCD1 complementary DNA (cDNA). Following administration of elivaldogene autotemcel, autologous CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) that migrate to the brain, where they can further differentiate into macrophages and cerebral microglia that can produce functional ALDP. Functional ALDPs can promote the local degradation of VLCFAs in the brain, stabilizing the course of the disease to prevent further inflammation and demyelination. Following successful engraftment with genetically modified cells, the expression of ALDP is expected to be life-long.

适应症

Elivaldogene autotemcel is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9.

• Neurologic Dysfunction