Research Roundup: September 10, 2021

Welcome to the September 10, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

MyoAAV is a potentially safer way to deliver therapeutic genes to muscle 

While some gene therapies that leverage gene-shuttling viruses have shown promise in treating some forms of muscular dystrophies, they can lead to serious side effects. Sharif Tabebordbar, Kim Lagerborg, Amy Wagers (Harvard), institute member Pardis Sabeti, and colleagues in the Infectious Disease and Microbiome Program have developed a family of viral vectors called MyoAAV that can deliver genetic cargo to mouse, primate, and human muscle cells with high selectivity and efficiency. MyoAAV can deliver therapeutic genes at doses around 100 to 250 times lower than other viral vectors used in clinical trials and preclinical studies, potentially reducing the likelihood of adverse side effects. Read more in Cell and a Broad news story and video. 

A new class of programmable gene-editing proteins

A team led by Han Altae-Tran, Soumya Kannan, and core institute member Feng Zhang has revealed a novel class of RNA-guided nucleases, named OMEGAs (Obligate Mobile Element Guided Activity), with strong potential for development as biotechnologies. These abundant and widespread proteins may be the ancestors of CRISPR-Cas9 and CRISPR-Cas12 systems. The researchers characterized several OMEGAs — including IscB and TnpB proteins, which are substantially smaller than Cas9 — and showed they can be reprogrammed to cleave target DNA, including in human cells. The work provides a starting point for potentially developing new, compact programmable molecular technologies. Read more in Science and an MIT news story.

Convection-enhanced insulin secretion

Macroencapsulation devices (MEDs) can serve as artificial pancreases for patients with type 1 diabetes, for whom insulin injections might not stabilize glucose levels. In MEDs, insulin-secreting β cells are transplanted into a patient inside a vehicle that protects the cells from immune rejection. However, many of these cells die or don’t produce insulin fast enough because they receive limited nutrients and oxygen through diffusion. In PNAS, postdoctoral researcher Kisuk Yang, associate member Jeffrey Karp of the Chemical Biology and Therapeutics Science Program, and colleagues describe convection-enhanced “ceMEDs” that rapidly stimulate insulin secretion through convection, can carry 10-fold more β cells than conventional MEDs, and reduce hyperglycemia in rats within two days. Learn more in a Brigham and Women’s news release. 

Markers of treatment response for prostate cancer

Patients being treated for high-risk localized prostate cancer show a wide range of responses to treatment. To understand what mediates such different responses, postdoctoral scholar Alok Tewari, associated researcher Alexander Cheung, and associate member Eliezer Van Allen in the Cancer Program performed whole exome and RNA sequencing of patient biopsies taken before neoadjuvant treatment and surgery. They found that tumors from clinically exceptional responders had SPOP mutations, SPOPL loss, and elevated androgen signaling, while those of non-responders had TP53 mutations, PTEN loss, and elevated TGF-β signaling. According to phylogenetic analysis of multi-regional biopsies, these mutations arise early in tumor development. Read more about how this information could help guide doctors' treatment selections in Cell Reports.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.