Mesoscale proximity labeling to study macro changes to chromatin occupancy.

Proximity labeling traditionally identifies interactomes of a single protein or RNA, though this approach limits mechanistic understanding of biomolecules functioning within complex systems. Here, we demonstrate a strategy for deciphering ligand-induced changes to global biomolecular interactions by enabling proximity labelling at the mesoscale, across an entire cellular system. By inserting nanoscale proximity labelling catalysts throughout chromatin, this system, MesoMap, provided new insights into how HDAC inhibitors regulate gene expression.

The Platform Identifies Drug-Like Probes that Regulate Endogenous Protein Levels within Physiological Contexts.

Traditional phenotypic drug discovery platforms have suffered from poor scalability and a lack of mechanistic understanding of newly discovered phenotypic probes. To address this, we created Endo- (EGS), a high-throughput enabled screening platform that identifies bioactive small molecules capable of regulating endogenous protein expression encoded by any preselected target gene within a biologically appropriate context. As a proof-of-concept, successfully identified drug candidates that up-regulate endogenous expression of neuronal a gene that causes a neurodevelopmental disorder when haploinsufficient.

IgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice.

The widespread pre-existing αAAV-Abs in humans pose a critical challenge in translation of AAV gene therapy. The IgG degrading enzyme of Streptococci (IdeS) is demonstrated to specifically cleave IgG of humans and other species (not mouse). This study developed a modified new modified IdeS protein product (IdeS).

Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

No treatment is available to address the unmet needs of mucopolysaccharidosis (MPS) IIIA patients. Targeting the root cause, we developed a new self-complementary adeno-associated virus 9 (scAAV9) vector to deliver the human -sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a miniature cytomegalovirus (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single intravenous (i.