Gene therapy for spinal muscular atrophy: the Qatari experience

Ali, Hossamaldein; Ibrahim, Khalid; Elsaid, Mahmoud F.; Mohamed, Reem; Abeidah, Mahmoud; Rawwas, Azhar Othman Al; Elshafey, Khaled; Almulla, Hajer; El‐Akouri, Karen; Al-Mulla, Mariam; Othman, Amna; Musa, Sara; Al‐Mesaifri, Fatma; Ali, Rehab; Shahbeck, Noora; Al‐Mureikhi, Mariam; Alsulaiman, Reem; Al‐Kaabi, Saad; Ben‐Omran, Tawfeg

doi:10.1038/s41434-021-00273-7

Cited by 31 publications

(25 citation statements)

References 20 publications

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“…All of the above experiments were conducted in adult mice. However, many potential applications require early age intervention (Gray, 2016;Privolizzi et al, 2021;Ali et al, 2021). Therefore, we investigated MaCPNS1/2 transduction in DRG in neonates using an alternative delivery route.…”

Section: Resultsmentioning

confidence: 99%

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

Chen

Kumar

Adams

et al. 2022

Neuron

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Section: Resultsmentioning

confidence: 99%

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

Chen

Kumar

Adams

et al. 2022

Neuron

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“…Data from the real-world setting support the efficacy of onasemnogene abeparvovec for the treatment of SMA. Clinical experience in the USA [27][28][29][30], Qatar [31], Germany [32,33], Austria [33], Poland [34] and Australia [35] confirmed that onasemnogene abeparvovec was associated with improvements in motor function [27][28][29][30][31][32][33][34][35], bulbar function [28-30, 33, 35] and pulmonary function [28,29,33,35] in patients with SMA. Interim results from the large (n = 117), prospective, multinational, observational RESTORE registry demonstrated that onasemnogene abeparvovec improved or maintained CHOP INTEND scores in patients aged ≥ 6 months with SMA [36].…”

Section: Real-world Outcomesmentioning

confidence: 99%

“…A single intravenous infusion of onasemnogene abeparvovec was generally well tolerated in clinical trials in patients with SMA type 1 [18][19][20]26] and pre-symptomatic SMA [21,22], in the real-world setting [27,28,[31][32][33][34][35][36], through a Global Managed Access Program (GMAP) in patients up to 2 years of age [37], and during post-marketing surveillance [11,12,38].…”

Section: Tolerability Of Onasemnogene Abeparvovecmentioning

confidence: 99%

Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Blair

2022

CNS Drugs

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Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy approved for the treatment of spinal muscular atrophy (SMA). Administered as a one-time intravenous infusion, onasemnogene abeparvovec uses the adeno-associated virus vector to deliver a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells. SMN1 encodes survival motor neuron protein, which is responsible for the maintenance and function of motor neurons. In clinical trials, onasemnogene abeparvovec improved event-free survival, motor function and motor milestone outcomes in patients with SMA, with these improvements maintained over the longer term (up to a median of ≈ 5 years). Onasemnogene abeparvovec was also associated with rapid age-appropriate achievement of motor milestones and improvements in motor function in children with pre-symptomatic SMA, indicating the benefit of early treatment. Onasemnogene abeparvovec was generally well tolerated. Hepatotoxicity is a known risk that can generally be mitigated with prophylactic prednisolone. In conclusion, onasemnogene abeparvovec represents an important treatment option for patients with SMA, particularly when initiated early in the course of the disease. Plain Language SummarySpinal muscular atrophy (SMA) is a rare genetic condition that causes muscle weakness and wasting. Infants with SMA type 1, the most common form of the disease, are unable to sit without support and usually die before the age of 2 years if untreated. SMA is caused by a defect in the survival motor neuron 1 (SMN1) gene. This gene provides instructions for making survival motor neuron protein, which is essential for the health and normal function of the nerves that control muscles. Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy that replaces the missing SMN1 gene and is given as a one-time infusion into a vein. In patients with SMA, onasemnogene abeparvovec improved event-free survival (alive without breathing support), motor function and achievement of motor milestones. Patients maintained these improvements for up to ≈ 5 years after treatment. Onasemnogene abeparvovec also helped pre-symptomatic children reach motor milestones at ages similar to healthy children. Onasemnogene abeparvovec is generally well tolerated and is an important treatment option for patients with SMA, including those who are yet to develop symptoms.

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“…Gene and cell-based therapies usually rely on stable expression of transgene to replace defective genes [ 1 , 2 ], enhance cell functions [ 3 ], and improve the safety of engineered cells [ 4 , 5 ]. However, most of the transgenes are delivered with lentivirus/retrovirus vectors and integrated into the genome in a random or semi-random manner [ 6 ], leading to unpredictable gene expression patterns, disruption of endogenous transcription, and malignancy [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Genomics and epigenetics guided identification of tissue-specific genomic safe harbors

Shrestha

Bag

et al. 2022

Genome Biol

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Background Genomic safe harbors are regions of the genome that can maintain transgene expression without disrupting the function of host cells. Genomic safe harbors play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited safe harbors have been identified. Results Here, we develop a framework to facilitate searches for genomic safe harbors by integrating information from polymorphic mobile element insertions that naturally occur in human populations, epigenomic signatures, and 3D chromatin organization. By applying our framework to polymorphic mobile element insertions identified in the 1000 Genomes project and the Genotype-Tissue Expression (GTEx) project, we identify 19 candidate safe harbors in blood cells and 5 in brain cells. For three candidate sites in blood, we demonstrate the stable expression of transgene without disrupting nearby genes in host erythroid cells. We also develop a computer program, Genomics and Epigenetic Guided Safe Harbor mapper (GEG-SH mapper), for knowledge-based tissue-specific genomic safe harbor selection. Conclusions Our study provides a new knowledge-based framework to identify tissue-specific genomic safe harbors. In combination with the fast-growing genome engineering technologies, our approach has the potential to improve the overall safety and efficiency of gene and cell-based therapy in the near future.

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Gene therapy for spinal muscular atrophy: the Qatari experience

Cited by 31 publications

References 20 publications

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Genomics and epigenetics guided identification of tissue-specific genomic safe harbors

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