Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Mendell, Jerry R.; Al-Zaidy, Samiah; Shell, Richard; Arnold, W.; Rodino‐Klapac, Louise R.; Prior, Thomas W.; Lowes, Linda; Alfano, Lindsay; Berry, Katherine; Church, Kathleen; Kissel, John T.; Nagendran, Sukumar; L’Italien, James; Sproule, Douglas M.; Wells, Courtney; Cardenas, Jessica; Heitzer, Marjet D.; Kaspar, Allan; Corcoran, Sarah; Braun, Lyndsey; Likhite, Shibi; Miranda, Carlos J.; Meyer, Kathrin; Foust, Kevin D.; Burghes, Arthur H.M.; Kaspar, Brian K.

doi:10.1056/nejmoa1706198

Cited by 1,870 publications

(1,772 citation statements)

References 23 publications

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“…The absence of such strong toxicity in the trial reported by Manno et al may be attributed to differences in vector serotype and dose (2e12 GC/kg versus 2e14 GC/kg). However, it is interesting to note that in a recent clinical trial for spinal muscular atrophy similarly large rAAV9 doses (2e14 GC/kg) were administrated intravenously and were well tolerated in a phase 1 [93], now progressing into a phase 3, clinical trial (ClinicalTrials.gov Identifier: NCT03505099). Although caution is warranted and necessitates further investigation, the response needs to be measured in order to put the wellbeing of patients first [94].…”

Section: Lessons Learned From Ex-vivo Successmentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Section: Lessons Learned From Ex-vivo Successmentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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“…ATAC combines FUS with replication-incompetent AAV vectors, an established method to stably transfect mammalian cells without integration into the target genome. AAV is widely used in neuroscience research, and has recently shown promise in the clinic [20][21][22][23][24] . When a gene of interest carried by AAV is encoded under an appropriate promoter, the expression of this gene can be restricted to a specific class of neurons 25 .…”

Section: Introductionmentioning

confidence: 99%

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

et al. 2018

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Neurological and psychiatric diseases often involve the dysfunction of specific neural circuits in particular regions of the brain. Existing treatments, including drugs and implantable brain stimulators, aim to modulate the activity of these circuits, but are typically not cell type-specific, lack spatial targeting or require invasive procedures. Here, we introduce an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, called acoustically targeted chemogenetics, or ATAC, uses transient ultrasonic opening of the blood brain barrier to transduce neurons at specific locations in the brain with virally-encoded engineered G-protein-coupled receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. We demonstrate this concept in mice by using ATAC to noninvasively modify and subsequently activate or inhibit excitatory neurons within the hippocampus, showing that this enables pharmacological control of memory formation. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds, thereby overcoming some of the key limitations of conventional brain therapies.

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“…In this short-term study, we did not observe CD4- or CD8-positive cell infiltration of treated muscle, but longer-term studies with more sensitive assays must be performed. Additionally, although production of large quantities of AAV9 poses a challenge, doses of 2 × 10 14 vg/kg have been successfully used in human gene therapy trials (35). …”

mentioning

confidence: 99%

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

Amoasii

Hildyard

et al. 2018

Science

444

383

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Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

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Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Cited by 1,870 publications

References 23 publications

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

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