Child Neurology: Pathologically Confirmed Thrombotic Microangiopathy Caused by Onasemnogene Abeparvovec Treatment for SMA

Abstract

Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy for spinal muscular atrophy (SMA). Although several cases of drug-induced thrombotic microangiopathy due to onasemnogene abeparvovec have been reported, none has been confirmed pathologically. Here, we present renal histopathologic findings of TMA due to onasemnogene abeparvovec. On day 5 after receiving onasemnogene abeparvovec, a 23-month-old girl with SMA type 1 developed thrombocytopenia, microangiopathic hemolytic anemia, liver dysfunction, acute kidney injury, and hypertension. She was diagnosed with TMA and received an increased dose of prednisolone, antihypertensives, diuretics, packed red blood cell and platelet transfusion, a single dose of eculizumab, four cycles of plasmapheresis, and intermittent and continuous hemodialysis. Her TMA resolved by day 30. On day 49, renal biopsy was performed. Light microscopy revealed proliferation of glomerular mesangial cells and matrix, with mesangiolysis, endothelial cell swelling, and partial double contours of the glomerular basement membrane. Electron microscopy showed endothelial injury, with edematous changes of the subendothelial spaces and neoformation of the basement membrane, without electron-dense depositions. These findings are compatible with the recovery phase of TMA. One year after drug administration, her motor function is improved. She can hold her posture against gravity and has neither dysphagia nor respiratory disturbance, but mild hypertension persists. Physicians should be vigilant regarding TMA as a severe side effect of onasemnogene abeparvovec treatment, especially when thrombocytopenia, hemolytic anemia, increased lactate dehydrogenase, or acute kidney injury is present.

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies

“…In the two children who did not survive the cause of death was not related to treatment. We did not observe any of the major serious adverse effects recently reported such as TMA 10 , 19 , 27 , 28 or liver failure, 19 , 20 irrespective of age or previous treatment.…”

Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors

“…Activation of complement is involved in adverse events such as inflammation and thrombocytopenia in high-dose systemic AAV gene therapy. 25 It is hypothesized that pre-existing anti-AAV antibodies enhance this process by forming immune complexes with AAV vectors and activating the classic complement pathway. 1 Although the introduction of NAb using IVIG could increase this risk, delivering AAV via ICM limits peripheral vector loads compared with systemic AAV delivery, which could reduce AAV-antibody interaction and any resultant complement activation.…”

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

“…131 Administration of prednisolone, the complement inhibitor eculizumab, diuretics, and in some cases even plasmapheresis were used to treat SMA patients who developed hepatotoxicity and TMA. [118][119][120]132 Moreover, preclinical studies in mice and NHPs showed that pretreatment with intravenous immunoglobulins may prevent the toxic transduction of the liver and other peripheral organs. 133 Another approach suggested to minimize the risk of toxic immune responses after gene therapy is to perform multiple injections of the therapeutic product at lower concentrations rather than a single high dose.…”

“…Rituximab, which depletes B‐cells, limiting antibody production, decreased immune responses in a clinical trial for familial amyotrophic lateral sclerosis (FALS), increasing the effectiveness of AAV9‐mediated RNAi against SOD1 131 . Administration of prednisolone, the complement inhibitor eculizumab, diuretics, and in some cases even plasmapheresis were used to treat SMA patients who developed hepatotoxicity and TMA 118–120,132 . Moreover, preclinical studies in mice and NHPs showed that pretreatment with intravenous immunoglobulins may prevent the toxic transduction of the liver and other peripheral organs 133 …”