Intrathecal administration of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): Phase 1/2A study (strong)

Finkel, R.; Day, John W.; Darras, Basil T.; Kuntz, Nancy L.; Connolly, AM; Crawford, Thomas O.; Butterfield, Russell J.; Shieh, PB; Tennekoon, Gihan; Iannaccone, Susan T.; Meriggioli, Matthew N.; Ogrinc, Francis G.; Kavanagh, Sarah; Kernbauer, Elaine; Whittle, Jason D.; L’Italien, James; Kaspar, Brian K.; Sproule, Douglas M.; Spector, Sidney A.; Feltner, Douglas E.; Mendell, Jerry R.

doi:10.1016/j.jns.2019.10.322

Cited by 13 publications

(14 citation statements)

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“…At the time of analysis (March 8, 2019), seven patients were not hospitalized or receiving additional care, and three patients had started adjuvant nusinersen therapy (114). Interim results of an ongoing open-label phase 1-2 clinical trial of intrathecal administration of onasemnogene abeparvovec in patients with three SMN2 copies (STRONG, NCT03381729) showed a sustained gain of motor milestones and, as the primary outcome, treatment safety (52).…”

Section: Small Moleculesmentioning

confidence: 99%

Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

Wirth

Karakaya

Kye

et al. 2020

Annu. Rev. Genom. Hum. Genet.

186

181

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Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease's phenotype–genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively. This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Small Moleculesmentioning

confidence: 99%

Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

Wirth

Karakaya

Kye

et al. 2020

Annu. Rev. Genom. Hum. Genet.

186

181

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“…Review of data 6–12 months after therapy showed no treated patients had lost motor milestones and some had gained milestones. 70 , 72 The trial was recently placed on a partial hold by the FDA recently given safety concerns from an animal model. 73 SPR1NT is an ongoing Phase III trial evaluating safety and efficacy of gene therapy administration to pre-symptomatic SMA patients with 2–3 copies of SMN2.…”

Section: Treatmentmentioning

confidence: 99%

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

Keinath¹,

Prior²,

Prior³

2021

TACG

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Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adenoassociated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.

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“…Bardzo mało jest badań dotyczących zastosowania onasemnogene abeparvovec u pacjentów cierpiących na SMA2 i SMA3. Wyniki I fazy badania klinicznego o nazwie STRONG, które przedstawiane były na konferencjach naukowych w kwietniu i maju 2019 r. wykazały, że lek ten jest bardzo dobrze tolerowany i ma znaczący wpływ na poprawę stanu zdrowia u pacjentów chorych na SMA2 i SMA3 [27].…”

Section: Badania Kliniczneunclassified

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

Majchrzak‐Celińska¹,

Warych²,

Szoszkiewicz³

2020

Farm Pol.

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Farmacja Polska, ISSN 0014-8261 (print); ISSN 2544-8552 (on-line) Spinal muscular atrophy -onasemnogene abeparvovec and other therapeutic optionsSpinal muscular atrophy (SMA) is a neuromuscular disorder that results in the loss of motor neurons. SMA is caused by mutations in the SMN1 gene, leading to the decreased synthesis of the SMN protein, necessary for motor neuron survival. In the past, SMA was considered to be an incurable disease, and therapy was limited only to symptomatic treatment. However, currently there are drugs which effectively inhibit the development of the disease, and even give hope for its cure. Their mechanism of action involves either delivering of a functional copy of the SMN1 gene, or modification of the alternative splicing of the SMN2 gene. Moreover, amelioration of muscle growth and increasing muscle contractility serves as a way of relieving the symptoms of the disease. The functional copy of SMN1 gene is delivered by onasemnogene abeparvovec (Zolgensma). The drug contains cDNA sequences, which correspond to the missing SMN1 gene. It is administered in the form of adeno-associated viral vector serotype 9 (AAV9)-based gene therapy, as a single intravenous infusion, to treat children less than 2 years old. Currently, the drug is approved only in the USA, and its cost exceeds PLN 2,000,000. SMN2 has nearly identical sequence as SMN1, however due to alternative splicing, only around 10% of its transcript results in a full-length, functional SMN protein.Modification of the alternative splicing of the SMN2 pre-mRNA by the drug nusinersen (Spinraza) results in an increased level of the SMN protein. Nusinersen is administered as intrathecal injections and is available both in the USA as well as in Europe. Also risdiplam and branaplam -small-molecule drugs with similar mechanism of action are now being tested in clinical trials. The inhibition of proMyostatin cleavage and slowing calcium release, leads to the increased muscle growth and contractility, respectively. So far, three promising drugs are being evaluated in clinical trials: SRK-015, which is a selective and local inhibitor of the activation of myostatin, as well as reldesemtiv (CK-2127107) and tirasemtiv (CK-2127107), both being the fast skeletal muscle troponin activators. These drugs do not affect the genetic cause of SMA, but relieve the symptoms of the disease. Early diagnosis and treatment gives hope for halting the progress of SMA, preserving motor function and extending patient's life.To jest artykuł o otwartym dostępie, na licencji CC BY NC https://creativecommons.org/licenses/by-nc/4.0/

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Intrathecal administration of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): Phase 1/2A study (strong)

Abstract: our model enables this for the investigation of new compounds in diseases involving demyelination.

Cited by 13 publications

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Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

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