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From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1

Published on Nov 1, 2019in Pediatric Neurology2.326
· DOI :10.1016/j.pediatrneurol.2019.06.007
Samiah Al-Zaidy8
Estimated H-index: 8
(OSU: Ohio State University),
Jerry R. Mendell80
Estimated H-index: 80
(OSU: Ohio State University)
Sources
Abstract
Abstract Spinal muscular atrophy is a devastating neurodegenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. Onasemnogene abeparvovec (Zolgensma, formerly AVXS-101) is a gene replacement therapy comprising an adeno-associated viral vector containing the human SMN gene under control of the chicken beta-actin promoter. This therapy addresses the genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnogene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying gene replacement therapy for spinal muscular atrophy, describes the onasemnogene abeparvovec clinical trial experience, and provides expert recommendations as a reference for the real-world use of onasemnogene abeparvovec in clinical practice. As of May 24, 2019, the Food and Drug Administration approved onasemnogene abeparvovec, the first gene therapy approved to treat children younger than two years with spinal muscular atrophy.
  • References (45)
  • Citations (3)
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References45
Newest
#1Christian Leborgne (French Institute of Health and Medical Research)H-Index: 22
#2Virginie Latournerie (French Institute of Health and Medical Research)H-Index: 3
Last. Philippe Veron (French Institute of Health and Medical Research)H-Index: 24
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Abstract Adeno-associated virus (AAV) vectors are promising candidates for gene therapy and have been explored as gene delivery vehicles in the treatment of Duchenne Muscular Dystrophy (DMD). Recent studies showed compelling evidence of therapeutic efficacy in large animal models following the intravenous delivery of AAV vectors expressing truncated forms of dystrophin. However, to translate these results to humans, careful assessment of the prevalence of anti-AAV neutralizing antibodies (NAbs) ...
4 CitationsSource
#1A HighKatherineH-Index: 73
#2Lindsey A. George (UPenn: University of Pennsylvania)H-Index: 8
Last. Kathleen B ReapeH-Index: 1
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Gene transfer for hemophilia A offers the potential for a one-time disease altering treatment, eliminating the risk of bleeds while freeing patients from the burden of lifelong chronic therapy. SPK-8011 consists of a bioengineered AAV capsid expressing B domain-deleted factor VIII (FVIII) under the control of a liver-specific promoter. In pre-clinical studies, we showed a dose-dependent increase in circulating FVIII levels in non-human primates infused with SPK-8011. We conducted a Phase I/II st...
7 CitationsSource
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbrevi...
30 CitationsSource
#2Jacinda B. Sampson (Stanford University)H-Index: 17
Last. Jill JareckiH-Index: 7
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31 CitationsSource
#1Wolfgang MiesbachH-Index: 19
#2Karina Meijer (UG: University of Groningen)H-Index: 28
Last. Frank W.G. Leebeek (EUR: Erasmus University Rotterdam)H-Index: 46
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Hemophilia B gene therapy aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multi-national, open-label study included ten adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested ...
46 CitationsSource
#1Pasqualina Colella (French Institute of Health and Medical Research)H-Index: 1
#2Giuseppe Ronzitti (French Institute of Health and Medical Research)H-Index: 9
Last. Federico Mingozzi (French Institute of Health and Medical Research)H-Index: 11
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In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, in...
72 CitationsSource
#1Dongsheng Duan (MU: University of Missouri)H-Index: 36
Whole body systemic gene therapy is likely the most effective way to greatly reduce the disease burden of Duchenne muscular dystrophy (DMD), an X-linked inherited muscle disease that leads to premature death in early adulthood. Genetically, DMD is due to null mutation of the dystrophin gene, one of the largest genes in the genome. Recent studies have shown highly promising improvements in animal models with intravascular delivery of the engineered micro-dystrophin gene by adeno-associated virus ...
10 CitationsSource
#1Savita RangarajanH-Index: 20
#2L WalshH-Index: 1
Last. K. J. PasiH-Index: 11
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BackgroundPatients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. MethodsWe infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain–deleted huma...
125 CitationsSource
#1Lindsey A. George (UPenn: University of Pennsylvania)H-Index: 8
#2Spencer K. SullivanH-Index: 12
Last. A HighKatherineH-Index: 73
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BackgroundThe prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. MethodsWe infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men...
129 CitationsSource
BackgroundSpinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. MethodsFifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA enc...
293 CitationsSource
Cited By3
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#1Andreas ZieglerH-Index: 86
Last. Afshin SaffariH-Index: 6
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Source
Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficien...
Source
#1Natalia N. Singh (Iowa State University)H-Index: 20
#2Eric W. Ottesen (Iowa State University)H-Index: 9
Last. Ravindra N. Singh (Iowa State University)H-Index: 28
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Abstract Human Survival Motor Neuron (SMN) genes code for SMN, an essential multifunctional protein. Complete loss of SMN is embryonic lethal, while low levels of SMN lead to spinal muscular atrophy (SMA), a major genetic disease of children and infants. Reduced levels of SMN are associated with the abnormal development of heart, lung, muscle, gastro-intestinal system and testis. The SMN loci have been shown to generate a vast repertoire of transcripts, including linear, back- and trans-spliced ...
Source
#1Wenfei Liu (UCL: University College London)H-Index: 1
#2Sophia-Martha kleine-Holthaus (UCL Institute of Ophthalmology)
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Abstract The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of rare monogenic neurodegenerative diseases predominantly affecting children. All NCLs are lethal and incurable and only one has an approved treatment available. To date, 13 NCL subtypes (CLN1-8, CLN10-14) have been identified, based on the particular disease-causing defective gene. The exact functions of NCL proteins and the pathological mechanisms underlying the diseases are still unclear. However, g...
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Objective: To review the efficacy and safety of onasemnogene abeparvovec-xioi (Zolgensma) in the treatment of spinal muscular atrophy (SMA). Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to December 2019) was completed using the terms onasemnogene, AVXS-101, and spinal muscular atrophy. Manufacturer prescribing information, article bibliographies, and data from ClinicalTrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All...
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#1Bryan Cwik (PSU: Portland State University)H-Index: 3
Design of clinical trials for germline gene editing stretches current accepted standards for human subjects research. Among the challenges involved is a set of issues concerning intergenerational monitoring—long-term follow-up study of subjects and their descendants. Because changes made at the germline would be heritable, germline gene editing could have adverse effects on individuals’ health that can be passed on to future generations. Determining whether germline gene editing is safe and effe...
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#1K. M. Chan (Harvard University)H-Index: 126
#1Casey A. Maguire (Harvard University)H-Index: 25
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Abstract Gene therapy using virus vectors to treat hereditary diseases has made remarkable progress in the past decade. There are FDA-approved products for ex-vivo gene therapy for diseases such as immunodeficiencies (e.g., SCID), and in vivo gene therapy for a rare blindness and neuro-muscular disease. Gene therapy for hereditary hearing loss has picked up pace in the past five years due to progress in understanding disease gene function as well as the development of better technologies such as...
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AbstractIntroduction: The development of adeno-associated virus (AAV) vectors as safe vehicles for in vivo delivery of therapeutic genes has been a major milestone in the advancement of gene therap...
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Die Gentherapie als Behandlungskonzept bei menschlichen Erkrankungen hat in den letzten Jahren Einzug in die klinische Medizin gehalten. Bislang sind in Europa bereits 6 Gentherapeutika zugelassen worden. Weitere Praparate, die in den USA bereits zugelassen sind, stehen auch in Europa kurz davor. Durch die Gentherapie konnten Verfahren der onkologischen Immuntherapie verbessert oder erst moglich gemacht werden. Kausale Therapien fur eine grose Zahl angeborener Erkrankungen werden entwickelt. Gen...
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#1Christina A. Pacak (UF: University of Florida)H-Index: 15
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