Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

Chand, Deepa H.; Mohr, Franziska; McMillan, Hugh J.; Tukov, Francis Fonyuy; Montgomery, Kyle H.; Kleyn, A. de; Sun, Rui; Tauscher-Wisniewski, Sitra; Kaufmann, Petra; Kullak‐Ublick, Gerd A.

doi:10.1016/j.jhep.2020.11.001

Cited by 192 publications

(144 citation statements)

References 26 publications

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“…Safety concerns may be allayed given the extensive clinical experience with AAV in gene therapy applications via local - including intramuscular - or systemic routes of administration, the latter often at doses exceeding the doses proposed here by 100 to 1000-fold. These systemic studies have highlighted the potential for moderate to severe dose-related events of hepatotoxicity (Chand et al, 2020). Unlike most of the vectors pursued in gene therapy studies, AAVrh32.33 is minimally hepatotropic, particularly with the low dose intramuscular injections presented here (Figure S8D).…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mouse and non-human primates

Zabaleta

Dai

Bhatt

et al. 2021

Preprint

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SummaryThe SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 million deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological and logistical attributes of the vaccine. Here, two adeno-associated viral (AAV)-based vaccine candidates demonstrate potent immunogenicity in mouse and nonhuman primates following a single injection. Peak neutralizing antibody titers remain sustained at 5 months and are complemented by functional memory T-cells responses. The AAVrh32.33 capsid of the AAVCOVID vaccine is an engineered AAV to which no relevant pre-existing immunity exists in humans. Moreover, the vaccine is stable at room temperature for at least one month and is produced at high yields using established commercial manufacturing processes in the gene therapy industry. Thus, this methodology holds as a very promising single dose, thermostable vaccine platform well-suited to address emerging pathogens on a global scale.

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Section: Discussionmentioning

confidence: 99%

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mouse and non-human primates

Zabaleta

Dai

Bhatt

et al. 2021

Preprint

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“…To prevent the disappearance of the therapeutic genetic material, a recurrent and J o u r n a l P r e -p r o o f straightforward option already successfully applied in both pre-clinical and clinical trials is the administration of immunosuppressive treatments. 137,139,140 However, all carry the associated risk of leaving the patient transiently immunocompromised and thus exposed to infection, and depending on the characteristics of the disease, this is a downside to be carefully evaluated.…”

Section: Retroviral and Lentiviral Vectorsmentioning

confidence: 99%

“…To prevent the disappearance of the therapeutic genetic material, a recurrent and straightforward option already successfully applied in both preclinical and clinical trials is the administration of immunosuppressive treatments. 137 , 139 , 140 However, all carry the associated risk of leaving the patient transiently immunocompromised and thus exposed to infection, and depending on the characteristics of the disease, this is a downside to be carefully evaluated. Several alternatives being explored are the use of polymer-coated vectors or the modification of the vector surface to prevent uptake by APCs and reduce the activation of the immune response and increase cell transduction.…”

Section: Relevant Aspects To Consider Current Limitations and Possible Future Directions In Liver-targeted Gene Therapymentioning

confidence: 99%

Novel vectors and approaches for gene therapy in liver diseases

Maestro

Weber²,

Zabaleta

et al. 2021

JHEP Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…73 Liver injury and hepatotoxicity can be serious without appropriate monitoring and intervention. 74 Feldman group had the highest mean costs ($25,517) followed by childhood onset ($6357) and late onset ($2499). In the matched cohort without SMA, the cost was significantly lower in the infantile group ($406), childhood onset ($188), and late onset ($742).…”

Section: Nusinersenmentioning

confidence: 99%

Spinal muscular atrophy: an update for managed care pharmacists

2021

Am J Manag Care

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It is estimated that about one in 65 people are carriers of the gene mutation for spinal muscular atrophy (SMA), which causes degeneration of motor neurons and progressive muscle weakness affecting patients' ability to move, swallow, and breathe. The rapid progression of SMA and high rate of mortality have contributed to its designation as a recommended condition for which all newborns should receive screening. The majority of patients with SMA present with signs and symptoms by 3 months of age, but symptom onset can vary according to SMA type, thus affecting treatment decisions and making early diagnosis and treatment initiation imperative. Previously, management of SMA consisted primarily of supportive care with specialized equipment, such as ventilators and feeding tubes, physical and occupational therapy, and other expert care to maintain patient quality of life, with astronomical associated costs. However, use of disease-modifying therapies has the potential to change existing treatment protocols, normalize development, and increase survival, especially for patients in whom a diagnosis was received early. These therapies are also associated with high costs and are often subject to extensive barriers to access. To balance the costs of treatment with improvement of patient outcomes, managed care professionals and pharmacists must establish a framework for evaluating newly approved therapies and expediting the use of these agents in the treatment of SMA. Statement of Educational Need Recent drug approvals for the treatment of spinal muscular atrophy (SMA) have prompted the development of treatment guidelines along with recommendations for genetic testing for diagnosis. Due to the rarity of SMA, and the historical lack of pharmacotherapy, managed care pharmacists may not have exposure to this highly morbid disease state and medications. Cost of treatment must be considered, and managed care pharmacists need to be provided with the appropriate tools to make the best evidence-based formulary decisions and develop appropriate utilization management strategies. Educational Objectives Upon completion of this activity, participants should be able to: • Determine gold standards for treating spinal muscular atrophy (SMA) including updates to the 2020 revised recommendations. • Use the most up-to-date clinical data of approved therapies to aid in advancing treatment options and patient-specific protocols for SMA. • Employ strategies that allow access to patient-specific treatment protocols and the potential opportunities to offset costs in SMA. Accreditation Statement Pharmacy Times Continuing Education™ is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.20 CEU) under the ACPE universal activity number 0290-0000-21-022-H01-P. The activity is available for CE credit through February 15, 2022. Obtaining Credit: Participants must read the article, complete the online posttest and an online evaluation and ...

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Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

Cited by 192 publications

References 26 publications

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mouse and non-human primates

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mouse and non-human primates

Novel vectors and approaches for gene therapy in liver diseases

Spinal muscular atrophy: an update for managed care pharmacists

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