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Gene therapy for spinal muscular atrophy: the Qatari experience.

ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma^®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

SUBMITTER: Ali HG

PROVIDER: S-EPMC8599021 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Gene therapy for spinal muscular atrophy: the Qatari experience.

Ali Hossamaldein Gaber HG Ibrahim Khalid K Elsaid Mahmoud Fawzi MF Mohamed Reem Babiker RB Abeidah Mahmoud I A MIA Al Rawwas Azhar Othman AO Elshafey Khaled K Almulla Hajer H El-Akouri Karen K Almulla Mariam M Othman Amna A Musa Sara S Al-Mesaifri Fatma F Ali Rehab R Shahbeck Noora N Al-Mureikhi Mariam M Alsulaiman Reem R Alkaabi Saad S Ben-Omran Tawfeg T

Gene therapy 20210719 10-11

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma<sup>®</sup>) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and ...[more]

PMID: 34276047

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Project description:BackgroundRecently gene therapy with onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy (SMA). As the experience from clinical trials is limited, there are still uncertainties for which patient population the treatment can be considered safe and effective.MethodsWe report our experience with eight consecutive patients with SMA who were treated with the standard dose of onasemnogene abeparvovec (1.1×1014 vg/kg) at the University Hospital Bonn, Germany. All patients received prophylactic immunosuppression with 1 mg/kg/d prednisolone for four weeks starting on the day before gene therapy.ResultsWe treated eight patients (4 male, 4 female, age range 10-37 months) with a body weight between 7.1 and 11.9 kg. All patients had 2 or 3 copies of the SMN2-gene and were previously treated with nusinersen. Following treatment with onasemnogene abeparvovec all patients showed a temporary increase of the body temperature and an increase of transaminase levels. In all but one patient it was necessary to increase or prolong the standard steroid dose to control the immune response. In one severe case, liver damage was associated with impaired liver function. This patient received a steroid pulse therapy for five days. Blood counts revealed asymptomatic thrombocytopenia (<150×109/L) in 6/8 patients and a significant increase of monocytes following gene therapy. Liver values and blood counts returned to almost normal levels during the post-treatment observation period. Troponin I increased above normal limit in 4/8 patients but was not associated with any abnormalities on cardiac evaluation.ConclusionsIn a broader spectrum of patients, treatment with onasemnogene abeparvovec was associated with a higher rate of adverse events. In our cases it was possible to control the immune response by close monitoring and adaptation of the immunosuppressive regimen. Further research is needed to better understand the immune response following gene therapy and ideally to identify patients at risk for a more severe reaction.

Project description:BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that, in most cases, involves homozygous deletion of the SMN1 gene. This causes a deficiency in survival motor neuron (SMN) protein, which plays a critical role in motor neuron development. SMA has a range of phenotype expression resulting in variable age of symptom onset, maximum motor strength achieved, and survival. Without intervention, infants with a more severe form of the disease (type 1 SMA) die before 2 years of age. Although it is rare, SMA is the most common fatal inherited disease of infancy, and until recently, treatment was primarily supportive. In 2016, a new agent, nusinersen, was approved by the FDA. Other treatments are in development, including a gene therapy, AVXS-101. These treatments are not only improving the lives of patients with SMA and their families, they are changing the disease phenotype. They have the greatest benefit when given early in the disease course.ObjectivesTo discuss current knowledge about SMA, provide clinical evidence for available and emerging treatment options, and present approaches for adding new therapies to hospital/health system formularies to ensure timely access to newly approved therapies for SMA.SummaryAdvances in clinical care have significantly extended the lives of individuals with SMA, and research into the genetic mechanisms leading to disease have revealed strategies for intervention that target the underlying cause of SMA. Nusinersen is now on the market, and other treatment options, such as AVXS-101, may soon be approved. This article provides an overview of SMA and the genetic mechanisms leading to SMN deficiency, then describes how new and emerging treatments work to overcome this deficiency and prevent associated nerve damage and disability. In addition, we discuss steps for incorporating AVXS-101 into hospital/health system formularies, along with barriers and concerns that may delay access, based in part on lessons learned with nusinersen.

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Gene therapy for spinal muscular atrophy: the Qatari experience.

Publications

Gene therapy for spinal muscular atrophy: the Qatari experience.

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