Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene therapy

Abstract

Adeno-Associated Virus (AAV) gene therapies are highly promising, such as the onasemnogene abeparvovec (Zolgensma®) in Spinal Muscle Atrophy (SMA). We report the first case of fatal systemic Thrombotic MicroAngiopathy (TMA) following onasemnogene abeparvovec in a 6-month-old child with SMA type 1, carrying a potential genetic predisposition in the Complement Factor I gene. Other cases of TMA have recently been reported after onasemnogene abeparvovec, and after AAV9 minidystrophin therapy in the Duchenne muscular dystrophy. The risk-benefit ratio of this therapy must therefore be assessed. Early recognition of TMA and targeted immunotherapy are fundamental to ensure the safety of patients treated with AAV gene therapies.

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

“…For viral vector-mediated gene delivery, there are ongoing concerns over capsid immunogenicity and toxicity. There have been recent reports of serious hepatotoxicity following AAV gene delivery, in XLMTM & SMN (54)(55)(56)(57). In parallel, lipid nanoparticles encapsulating mRNA is emerging as a promising therapy for liver monogenic diseases (58)(59)(60).…”

Is gene therapy in spinal muscular atrophy safe? A casereport of thrombotic microangiopathy following onasemnogene abeparvovec

“…infectious) etiologic factors, which altogether lead to activation and dysregulation of the alternate complement pathway [3][4]. The severity of the symptoms of TMA vary (it is especially dangerous when it occurs rapidly after treatment) [5]. Our patient experienced mild TMA with few physical signs.…”

“…However, reviewing the literature, we found cases of patients with TMA after onasemnogene abeparvovec therapy complicated with infections, pericardial effusion and severe hypertension [4]. A case of death in the course of post-gene therapy TMA has also been reported [5]. It is therefore recommended to evaluate predisposing factors for TMA, such as infections (shiga toxin), ADAMTS-13 activity and gene mutations [3] [5].…”

“…It is therefore recommended to evaluate predisposing factors for TMA, such as infections (shiga toxin), ADAMTS-13 activity and gene mutations [3] [5]. The possible mutations responsible for the severe course of TMA involve the CFI, FAT1 and ACTN4 genes [5]. Since no gene screening for these mutations is available, parents should be informed about the risks of gene therapy [5].…”

“…The possible mutations responsible for the severe course of TMA involve the CFI, FAT1 and ACTN4 genes [5]. Since no gene screening for these mutations is available, parents should be informed about the risks of gene therapy [5].…”