AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice.

The SLC6A1 gene encodes the gamma-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed two AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1 KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1-/- or Slc6a1+/- mice, as well as improvement in several behavioral phenotypes of Slc6a1-/- mice.

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease.

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dose-dependent effects.

Current knowledge of SLC6A1-related neurodevelopmental disorders.

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder and intellectual disability. The solute carrier family 6 member 1 gene encodes for the GABA transporter protein type 1, which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures.

Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma.

Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models.

The Organophosphorus Pesticide Chlorpyrifos Induces Sex-Specific Airway Hyperreactivity in Adult Rats.

Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. Although the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans.

BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling.

Dendritic morphology is a critical determinant of neuronal connectivity, and in postganglionic sympathetic neurons, tonic activity correlates directly with the size of the dendritic arbor. Thus, identifying signaling mechanisms that regulate dendritic arborization of sympathetic neurons is important to understanding how functional neural circuitry is established and maintained in the sympathetic nervous system. Bone morphogenetic proteins (BMPs) promote dendritic growth in sympathetic neurons; however, downstream signaling events that link BMP receptor activation to dendritic growth are poorly characterized.