AVXS-101 phase 1 gene therapy clinical trial in SMA Type 1: end-of-Study event free survival and achievement of developmental milestones

Mendell, J. R.; Al-Zaidy, Samiah; Shell, Richard; Arnold, W. David; Rodino‐Klapac, Louise R.; Prior, Thomas W.; Lowes, L.; Alfano, Lindsay; Berry, Katherine; Church, Kathleen; Kissel, John T.; Nagendran, Sukumar; L’Italien, James; Sproule, D.M.; Wells, Courtney; Burghes, Arthur; Foust, K.; Kaspar, Brian K.

doi:10.1016/j.nmd.2017.06.412

Cited by 10 publications

(6 citation statements)

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“…Achieving a diagnosis is always important, not only for genetic counseling but also to implement disease-specific standards of care [17,20,21]. The recent advent of new therapeutic options, already commercially available, has further increased the need to confirm diagnosis as early as possible as early treatment has been associated with better outcome [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

et al. 2020

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Background The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. Methods All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. Results The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD ±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. Conclusions Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available

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Section: Introductionmentioning

confidence: 99%

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

et al. 2020

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“…9,10 Longitudinal studies for patients treated with nusinersen are still ongoing and will provide additional insights to confirm its long-term efficacy and safety. 4 In the meantime, other potential therapies for SMA type 1 are under clinical investigation and show promising preliminary results, including the SMN1 gene replacement AVXS-101 (Zolgensma; AveXis, Novartis, Chicago, IL) 11,12 and the modulator of SMN2 splicing RO7034067 (Risdiplam; Roche, Basel, Switzerland; trial #NCT02913482). 13 These emerging therapies, in conjunction with standardized respiratory, orthopedic, and nutritional support, will continue to improve morbidity and survival in even the weakest patients with SMA type 1.…”

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confidence: 99%

Impaired kidney structure and function in spinal muscular atrophy

et al. 2019

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ObjectiveTo determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls.MethodsIn this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls.ResultsPatients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and crystals in urine, and nephrocalcinosis and fibrosis. Nephrotoxicity and polycystic kidney disease PCR arrays revealed multiple differentially expressed genes, and immunoblot analysis showed decreased calcium-sensing receptors and calbindin and increased insulin-like growth factor–binding proteins in kidneys from patients with SMA.ConclusionsThese findings demonstrate that patients with SMA type 1, in the absence of disease-modifying therapies, frequently manifest impaired renal function as a primary or secondary consequence of their disease. This study provides new insights into systemic contributions to SMA disease pathogenesis and the need to identify coadjuvant therapies.

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“…Even though some vectors can cross the BBB, the target tissue concentration after systemic delivery is often not therapeutically relevant. Nevertheless, a successful clinical trial with systemic administration was performed by AveXis to treat children with SMA (Mendell et al, 2017). The vector used was a self-complementary AAV9 and following systemic administration a therapeutic effect in motor neurons in the spinal cord was observed.…”

Section: Aavs For Gene Transfer To the Nervous Systemmentioning

confidence: 99%

“…Non-viral delivery methods using nanoparticles or ASOs can also deliver therapeutic agents but the need for recurrent injections can become overwhelming and increase the risk for infections in patients. Nevertheless, ASOs have shown to be efficient and safe in animal models and have led to the initiation of several clinical trials for SOD1-ALS, C9orf72-ALS, and SMN2 for SMA Meyer et al, 2015;Mendell et al, 2017).…”

Section: Safety and Delivery Of Gene Therapy To Patientsmentioning

confidence: 99%

Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock

Martier

Konstantinova

2020

Front. Neurosci.

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Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.

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AVXS-101 phase 1 gene therapy clinical trial in SMA Type 1: end-of-Study event free survival and achievement of developmental milestones

Cited by 10 publications

References 0 publications

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

Impaired kidney structure and function in spinal muscular atrophy

Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock

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