Muscle-directed AAV gene therapy rescues the maple syrup urine disease phenotype in a mouse model

Greig, Jenny A.; Jennis, Matthew; Dandekar, Aditya; Chorazeczewski, Joanna K.; Smith, Melanie K.; Ashley, Scott N.; Yan, Hanying; Wilson, James M.

doi:10.1016/j.ymgme.2021.08.003

Cited by 12 publications

(11 citation statements)

References 26 publications

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“…These results suggest that the vaccine did not cause blood toxicity after injection. On the other hand, we found that the AAV was expressed in the liver of C57BL/6J mice (Figure S1c), which was also supported by other studies 19,20,21 . Similarly, we detected SRBD expression in the livers of the high-dose macaques, but very little in the low-dose group.…”

supporting

confidence: 90%

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Tong

Zhang

et al. 2022

Protein &Amp; Cell

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Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides longterm protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptorbinding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected preexisting AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.

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supporting

confidence: 90%

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Tong

Zhang

et al. 2022

Protein &Amp; Cell

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“…Proofs of concepts of efficacy of AAV gene therapy were recently published by us and others in a severe Bckdha À/À and in a mild Dbt À/À MSUD mouse models. 20,21 In this study, we extended this approach to the third MSUD gene, BCKDHB, mutated in 35% of patients, 2 with extensive characterization of a Bckdhb À/À mouse model and demonstration that AAV gene therapy expressing the human BCKDHB gene can achieve long-term rescue of the severe MSUD phenotype. This work now completes the supply of gene therapy products for the 3 MSUD genes.…”

Section: Discussionmentioning

confidence: 99%

“…This strategy was tested in a mild MSUD mouse model with injections at P21-P28. 21 To perform comparable experiments in severe MSUD models, bridging therapies are required to maintain the mice alive long enough. Alternatively, a severe conditional MSUD model inducible in adulthood could be of interest.…”

Section: Discussionmentioning

confidence: 99%

“…For MSUD, two proofs of concept studies of AAV gene therapy efficacy in mice have been recently published. 20,21 In a Bckdha À/À mouse model, which recapitulates the severe human MSUD phenotype, we tested two vectors, carrying the human version of BCKDHA gene under the control of either an ubiquitous EF1α or liver-specific hAAT promoter, encapsidated in AAV capsids of serotype 8 which mainly targets the liver but also other organs (such as heart), and injected at birth. We demonstrated that intravenous neonatal gene therapy with the AAV8-EF1α-hBCKDHA vector achieved sustained disease rescue while the AAV8-hAAT-hBCKDHA vector showed a more limited efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Successful treatment of severe MSUD in Bckdhb^−/− mice with neonatal AAV gene therapy

Pontoizeau

Gaborit

Tual

et al. 2023

J of Inher Metab Disea

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Maple syrup urine disease (MSUD) is rare autosomal recessive metabolic disorder caused by the dysfunction of the mitochondrial branched‐chain 2‐ketoacid dehydrogenase (BCKD) enzyme complex leading to massive accumulation of branched‐chain amino acids and 2‐keto acids. MSUD management, based on a life‐long strict protein restriction with nontoxic amino acids oral supplementation represents an unmet need as it is associated with a poor quality of life, and does not fully protect from acute life‐threatening decompensations or long‐term neuropsychiatric complications. Orthotopic liver transplantation is a beneficial therapeutic option, which shows that restoration of only a fraction of whole‐body BCKD enzyme activity is therapeutic. MSUD is thus an ideal target for gene therapy. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD, BCKDHA and DBT. In this study, we developed a similar approach for the third MSUD gene, BCKDHB. We performed the first characterization of a Bckdhb−/− mouse model, which recapitulates the severe human phenotype of MSUD with early‐neonatal symptoms leading to death during the first week of life with massive accumulation of MSUD biomarkers. Based on our previous experience in Bckdha−/− mice, we designed a transgene carrying the human BCKDHB gene under the control of a ubiquitous EF1α promoter, encapsidated in an AAV8 capsid. Injection in neonatal Bckdhb−/− mice at 1014 vg/kg achieved long‐term rescue of the severe MSUD phenotype of Bckdhb−/− mice. These data further validate the efficacy of gene therapy for MSUD opening perspectives towards clinical translation.

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“…Ectopic tissues, such as skeletal muscle, have been proposed as an alternative target for gene therapy. Greig and co-workers recently evaluated the efficacy of muscle and liver gene therapy [ 186 ]. AAV gene therapy based on the transfer of human BCKDHA or BCKDHB has been developed during the immediate neonatal period in MSUD animals [ 3 ].…”

Section: Maple Syrup Urine Diseasementioning

confidence: 99%

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

et al. 2022

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The majority of monogenic liver diseases are autosomal recessive disorders, with few being sex-related or co-dominant. Although orthotopic liver transplantation (LT) is currently the sole therapeutic option for end-stage patients, such an invasive surgical approach is severely restricted by the lack of donors and post-transplant complications, mainly associated with life-long immunosuppressive regimens. Therefore, the last decade has witnessed efforts for innovative cellular or gene-based therapeutic strategies. Gene therapy is a promising approach for treatment of many hereditary disorders, such as monogenic inborn errors. The liver is an organ characterized by unique features, making it an attractive target for in vivo and ex vivo gene transfer. The current genetic approaches for hereditary liver diseases are mediated by viral or non-viral vectors, with promising results generated by gene-editing tools, such as CRISPR-Cas9 technology. Despite massive progress in experimental gene-correction technologies, limitations in validated approaches for monogenic liver disorders have encouraged researchers to refine promising gene therapy protocols. Herein, we highlighted the most common monogenetic liver disorders, followed by proposed genetic engineering approaches, offered as promising therapeutic modalities.

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Muscle-directed AAV gene therapy rescues the maple syrup urine disease phenotype in a mouse model

Cited by 12 publications

References 26 publications

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Successful treatment of severe MSUD in Bckdhb^−/− mice with neonatal AAV gene therapy

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

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Muscle-directed AAV gene therapy rescues the maple syrup urine disease phenotype in a mouse model

Cited by 12 publications

References 26 publications

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Successful treatment of severe MSUD in Bckdhb−/− mice with neonatal AAV gene therapy

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

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Product

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Successful treatment of severe MSUD in Bckdhb^−/− mice with neonatal AAV gene therapy