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

Chen, Xinhong; Kumar, Sripriya Ravindra; Adams, Cameron D.; Yang, Dae Suk; Wang, Tongtong; Wolfe, Damien A.; Arokiaraj, Cynthia M.; Ngo, Victoria; Campos, Lillian; Griffiths, Jessica; Ichiki, Takako; Mazmanian, Sarkis K.; Osborne, Peregrine B.; Keast, Janet R.; Miller, Cory T.; Fox, Andrew S.; Chiu, Isaac M.; Gradinaru, Viviana

doi:10.1016/j.neuron.2022.05.003

Cited by 67 publications

(66 citation statements)

References 82 publications

(95 reference statements)

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“…Transduction of the human heart was 30-fold higher than that observed in preclinical studies in the porcine heart, despite the fact that pigs are widely considered and used as the physiologically most relevant large animal model for human heart disease and corresponding AAV vector development (abstract 1213). Last, as most recently illustrated by Chen et al (58), it is possible to evolve synthetic AAV capsids in rodents that also perform well in multiple different NHP models, in this example, the peripheral nervous system of mice, rats, marmosets, and macaques. On the one hand, capsids that are widely active across small and large animal species offer benefits with respect to preclinical characterization including toxicity studies and are thus desirable.…”

Section: Discussionmentioning

confidence: 93%

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders

et al. 2022

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Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors—AAVMYO2 and AAVMYO3—prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.

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Section: Discussionmentioning

confidence: 93%

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders

et al. 2022

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“…This data-maximalist approach will allow us to develop increasingly granular assessments of subjects’ behavior at a temporal resolution that would be impractical and prohibitively time-consuming to achieve by hand. Such granularity will grow more important as NHP researchers continue developing neuro-scientific strategies 97,98 that enable millisecond-resolution techniques like optogenetics 99 and fiber photometry 100 in studies of NHP behavior.…”

Section: Discussionmentioning

confidence: 99%

Rhesus Infant Nervous Temperament Predicts Peri-Adolescent Central Amygdala Metabolism & Behavioral Inhibition Measured by a Machine-Learning Approach

Holley

Campos

Zhang

et al. 2022

Preprint

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Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc), a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST), as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders, and how this relationship is mediated by alterations in the EAc, could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.

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“…Viral vector based regulation of some miRNAs could also remarkably ameliorate pathological remodeling ( 14 , 120 ). A group of reported engineered AAVs could specifically deliver genes to rodent and non-human primate nervous system recently ( 121 ); developing engineered AAVs for ncRNAs delivery to CMs or CFs is one of the promising directions in the future.…”

Section: Therapeutic Potential Of Non-coding Rnas For Cardiac Fibrosismentioning

confidence: 99%

Non-coding RNAs: Important participants in cardiac fibrosis

Dong

Peng

Dong

et al. 2022

Front. Cardiovasc. Med.

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Cardiac remodeling is a pathophysiological process activated by diverse cardiac stress, which impairs cardiac function and leads to adverse clinical outcome. This remodeling partly attributes to cardiac fibrosis, which is a result of differentiation of cardiac fibroblasts to myofibroblasts and the production of excessive extracellular matrix within the myocardium. Non-coding RNAs mainly include microRNAs and long non-coding RNAs. These non-coding RNAs have been proved to have a profound impact on biological behaviors of various cardiac cell types and play a pivotal role in the development of cardiac fibrosis. This review aims to summarize the role of microRNAs and long non-coding RNAs in cardiac fibrosis associated with pressure overload, ischemia, diabetes mellitus, aging, atrial fibrillation and heart transplantation, meanwhile shed light on the diagnostic and therapeutic potential of non-coding RNAs for cardiac fibrosis.

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

Cited by 67 publications

References 82 publications

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders

Rhesus Infant Nervous Temperament Predicts Peri-Adolescent Central Amygdala Metabolism & Behavioral Inhibition Measured by a Machine-Learning Approach

Non-coding RNAs: Important participants in cardiac fibrosis

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