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AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset

Goertsen et al., Nature Neuroscience. 2021.

https://www.nature.com/articles/s41593-021-00969-4

Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.

Evidence in Primates Supporting the Use of Chemogenetics for the Treatment of Human Refractory Neuropsychiatric Disorders

Roseboom et al., Molecular Therapy. 2021.

https://doi.org/10.1016/j.ymthe.2021.04.021

A rhesus macaque model for pathological anxiety was used to investigate the feasibility of decreasing anxiety using chemogenetics, known as DREADDs (designer receptors exclusively activated by designer drugs), to reduce amygdala neuronal activity. A low-dose clozapine administration strategy was developed to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in the chemogentic monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology. Supported by ORIP (P51OD011106), NIMH, and NICHD. 

The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders

Subburaju et al., ACS Chemical Neuroscience. 2021.

https://pubs.acs.org/doi/full/10.1021/acschemneuro.1c00094

The dopamine D2 receptor exists in two different states, D2high and D2low; the former is the functional form of the D2 receptor and associates with intracellular G-proteins. The D2 agonist [3H]MCL-536 has high affinity for the D2 receptor (Kd 0.8 nM) and potently displaces the binding of (R-(-)-N-n-propylnorapomorphine (NPA; Ki 0.16 nM) and raclopride (Ki 0.9 nM) in competition binding assays. The authors characterized [3H]MCL-536. [3H]MCL-536 as metabolically stable. In vitro autoradiography on transaxial and coronal brain sections showed specific binding of [3H]MCL-536. [3H]MCL-536's unique properties make it a valuable tool for research on neurological disorders like Parkinson's disease or schizophrenia. Supported by ORIP (R43OD020186, R44OD024615) and NIMH.