Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue

Thomsen, Gretchen M.; Burghes, Arthur H.M.; Hsieh, Caroline; Do, Janet; Chu, Binh T. T.; Perry, Stephanie T.; Barkho, Basam Z.; Kaufmann, Petra; Sproule, Douglas M.; Feltner, Douglas E.; Chung, Wendy K.; McGovern, Vicki L.; Hevner, Robert F.; Conces, Miriam; Pierson, Christopher R.; Scoto, Mariacristina; Muntoni, Francesco; Mendell, Jerry R.; Foust, Kevin D.

doi:10.1038/s41591-021-01483-7

Cited by 66 publications

(70 citation statements)

References 59 publications

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Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…A phase 1 trial showed that, in patients with infantile-onset SMA, a single intravenous injection of onasemnogene abeparvovec resulted in longer survival and superior achievement of motor milestones in comparison with natural history [ 26 ]. Two phase 3 clinical trials also showed safety and efficacy of commercial-grade onasemnogene abeparvovec [ 27 , 28 ]; a recent study confirmed widespread induction of SMN protein expression throughout the CNS and peripheral organs [ 29 ].…”

Section: Nucleic Acid-based Therapeutic Approach For Neurological Disordersmentioning

confidence: 99%

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

Hirunagi

Sahashi

Meilleur

et al. 2022

Genes

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The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA.

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“…A recent report conducted on a mouse model of SMA confirms the lifelong need of SMN in all tissues, including peripheral tissues (Zhao et al, 2021 ). The first study performed on the postmortem tissues of SMA patients treated with gene therapy showed body-wide delivery of onasemnogene (Thomsen et al, 2021 ). However, distribution was uneven based on the counts of the AAV9 copy number per diploid genome.…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

“…The study was conducted with only two SMA patient samples and result showed patient to patient variability. One of the patients had degraded RNA that could not be reliably used for determining the SMN transcripts generated from the onasemnogene (Thomsen et al, 2021 ). Based on the experiments conducted on a single onasemnogene treated patient sample, authors found non-uniform expression of SMN transcripts in different tissues (Thomsen et al, 2021 ).…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy

Rossoll

Singh

2022

Front. Cell. Neurosci.

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Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue

Cited by 66 publications

References 59 publications

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

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

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy

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