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

Discussion

SMA is a neurodegenerative disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. This gene encodes the survival motor neuron (SMN) protein, which is essential for the normal functioning and survival of motor neurons. SMA type 1 is a severe form of SMA, resulting in muscle weakness and severe wasting from early infancy and failure to achieve major motor milestones during development. The majority of SMA1-affected infants require feeding and ventilatory support by age 14 months and have a life expectancy of less than 2 years without intervention.⁶ In 2016, the Food and Drug Administration (FDA) approved nusinersen, an antisense oligonucleotide.⁷ In 2020, risdiplam, another small molecule, received FDA approval.⁸ Onasemnogene abeparvovec, which was approved by the FDA in 2019, is an adeno-associated virus (AAV) vector-based gene therapy for SMA.⁹ It delivers a fully functional copy of human SMN1 via a self-complementary AAV9 vector. A 1-time IV administration of onasemnogene abeparvovec results in the production of the SMN protein in a child's motor neuron cells.¹⁰ Well-known side effects of the drug are fever, vomiting, acute liver injury, transient thrombocytopenia, and increased troponin I.⁹

TMA is characterized by its clinical presentation, which includes thrombocytopenia, microangiopathic hemolytic anemia, and organ damage including acute kidney injury. Primary acquired TMA syndromes include Shiga toxin–mediated TMA, ADAMTS13 deficiency–mediated TMA, complement-mediated TMA, and DITMA.¹¹ The current diagnosis criteria for TMA do not include renal biopsy. Although several cases of DITMA due to onasemnogene abeparvovec have been reported,¹² none provided pathologic confirmation or addressed the long-term prognosis. Because we needed to evaluate our patient's future treatment plan and prognosis in light of her renal pathology, we performed renal biopsy. The biopsy showed only a few sclerosing glomeruli, thus supporting the absence of diffuse global glomerulosclerosis and a relatively good prognosis without additional treatment.

We compare features of our current case of TMA caused by onasemnogene abeparvovec with 3 previously reported cases (Table 1).¹² None of the cases yielded enterohemorrhagic Escherichia coli from stool cultures. ADAMTS13 activity was normal in all 4 cases. Activation of the alternative complement pathway occurred in 2 of the 3 previous cases but not in our patient. Infection before or after administration of onasemnogene abeparvovec occurred in our patient and in 2 of the 3 previous cases. Immune responses to infection might have triggered the development of TMA.

Our patient received several doses of nusinersen before the administration of onasemnogene abeparvovec. We discontinued nusinersen after onasemnogene abeparvovec treatment in part because of limitations prescribed in the public health insurance of Japan. Two of the 3 previous cases were treated with nusinersen before onasemnogene abeparvovec.¹² Whether the preliminary administration of nusinersen in our patient led to a drug interaction with onasemnogene abeparvovec is unclear.

Treatment of DITMA consists of drug discontinuation and supportive care. As in our case, some patients have been treated with plasma exchange, anticomplementary therapy such as eculizumab, and immunosuppressive therapy such as increased glucocorticoid dosage. This combination therapy may be beneficial in cases of TMA due to onasemnogene abeparvovec, considering our patient's recovery from severe symptoms. DITMA has been classified into 2 categories: immune mediated and toxicity mediated.¹³ The former leads rapidly to renal failure, whereas the latter has a course lasting over several weeks or months. Given the acute exacerbation of our patient's symptoms, we hypothesize that onasemnogene abeparvovec led to TMA via the immune-mediated mechanism. Among the 15 patients given AAV9 vector–based drugs in Duchenne Muscular Dystrophy clinical trials, 4 cases of TMA have been reported.¹⁴ This finding suggests that ingredients common to both drugs may contribute to the induction of TMA. Likewise, hepatotoxicity, one of the major adverse events of onasemnogene abeparvovec, is thought to result from an immune response to AAV9 capsids.¹⁵ However, considering the frequency, timing of onset, duration, and biodistribution of the drug,⁴ the pathogenesis of drug-associated liver injury may be different from that of DITMA.

In the current case, TMA caused by onasemnogene abeparvovec was confirmed through pathology. We believe that the pathologic findings in this case report will help to elucidate the pathologic mechanism underlying DITMA due to onasemnogene abeparvovec. According to the manufacturer, as of July 2021, this drug has been administered in more than 1,400 cases of pediatric SMA, among which 9 cases of TMA have been documented.¹⁴ TMA requires urgent treatment to avoid irreversible organ damage or death. Because it occurs in most patients after onasemnogene abeparvovec administration, thrombocytopenia alone is insufficient to prompt a suspicion of TMA. Particularly in children with previous nusinersen exposure, it is not uncommon for the platelet count to drop below 50,000/µL in the absence of TMA after onasemnogene abeparvovec administration.³ Therefore, other potential signs of TMA should be monitored. Patients should be followed for signs of microangiopathic hemolytic anemia, such as anemia with crushed red blood cells, elevated LDH and indirect bilirubin, and signs of acute kidney injury, including hypertension, anuria, hematuria, elevated creatinine, and electrolyte abnormalities. Physicians should be vigilant regarding TMA as a possible severe side effect of onasemnogene abeparvovec treatment.