PCSK9 Inhibitor Treatment for Patients With SPG5

Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7a-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower cholesterol levels. Evolocumab, a member of this class, is a fully human monoclonal antibody that reduces LDL cholesterol levels by approximately 60%. We thus performed this interventional trial with Evolocumab 420 mg for SPG5 patients.

Cholesterol is initially side chain oxidized and the resulting 27-hydroxycholesterol (27-OHC) are 7a-hydroxylated

Inclusion Criteria: Age 14-80 years Probands with clinically manifest hereditary spastic paraplegia Genetically confirmed diagnosis of SPG5 Exclusion Criteria: Comprised treatment with statins 3 months prior to enrolment Contraindications to PCSK9 inhibitor therapy Pregnancy was excluded in women of childbearing age