Cells

Adeno-associated viral vectors (AAV) are the leading gene therapy in the clinic. AAV9 has been of particular interest due to its wide tropism for multiple tissue types as well as being able to cross the blood-brain barrier and transduce central nervous system tissues. However, effectively and safely targeting extrahepatic tissue following the systemic administration of AAV9 remains a challenge due to high rates of liver transduction and liver toxicity. Thus, a crucial first step in developing a safe AAV9-based vector is to reduce liver targeting. Here we utilized rational design techniques to make five point mutations in the AAV9 capsid. In doing so, we developed a novel AAV9 variant, AAV9-DM, that is characterized by reduced liver tropism as compared to AAV9 and other liver de-targeted AAV9 mutants. We show that AAV9-DM is effective at transducing cells in vivo, resulting in robust transgene expression over a 9-week period. Importantly, the AAV9-DM capsid maintains the ability to transduce non-hepatic tissues with a biodistribution similar to AAV9. This new mutant represents a novel AAV capsid that may be the basis for developing safer therapeutics to target extrahepatic tissue while reducing adverse side effects related to liver transduction.

The therapeutic interventions for pulmonary arterial hypertension (PAH) have predominantly focused on facilitating pulmonary blood flow by inducing vasodilation to reduce the mechanical resistance against the right ventricle (RV) [...]

Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances. The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology. Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization. Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders. Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions. Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy.