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Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery

Clinical report on a boy who developed a brain tumor after AAV gene therapy for treating his mucopolysaccharidosis (MPS). Fortunately, the boy has so far survived and thrived despite the MPS, the cancer, and the surgery to remove the tumor. Molecular analysis of the tumor revealed that it was caused by integration of parts of the AAV’s DNA into the genome, triggering overexpression of an oncogene called PLAG1. This case highlights the clinical importance of rare integration events in AAV gene therapy and reminds us that we must remain vigilant of the risks from these treatments.

Recombinant adeno-associated virus (AAV) vectors are predominantly nonintegrating, but rare genomic integration events have been associated with oncogenesis in neonatal murine models. Here we report a case of a neuroepithelial tumor that developed in a 5-year-old boy with severe mucopolysaccharidosis type I (MPSI, Hurler subtype) 4 years after intracisternal magna administration of AAV serotype 9 gene therapy. The patient underwent successful resection of the primary tumor. Postoperatively, he has continued to have advanced cognitive function for his age, a finding that indicates mitigation of MPSI. Molecular analysis of the tumor showed clonal integration of rearranged AAV vector elements into the gene PLAG1 and expression of a chimeric AAV-PLAG1 transcript.

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling

An unexpected and potentially big finding:

A single mitochondrial protein has an outsized role, acting as a central node, coordinating our circadian clock, temperature, dietary cues, sleep/wake cycle to control brown fat metabolism.

Brown/beige fat burns energy to keep the body warm and is linked to metabolic health. Its activity follows a daily rhythm (high when you’re awake, low during sleep), but it can also ramp up *suddenly* in response to cold weather or a fatty meal. How one system handles both scheduled and surprise demands was a mystery — until now.

The answer: one mitochondrial protein, SLC25A34.

The researchers found that three different signals — the circadian clock, diet, and temperature — all funnel through a single orphan mitochondrial transporter called SLC25A34.

How it works:

- During sleep: The circadian clock proteins REV-ERBα/β shut off SLC25A34 production.

Continue reading “Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling” | >

Common Viral Infections May Accelerate ALS

“A lot of the previous work in this area has been epidemiological in nature, without much focus on the molecular mechanisms that actually underpin the connection between infections and ALS,” says Ahmed, who co-first authored the new paper with Miller Lab alumni Art Marzok and Jonathan Mapletoft. “What makes our study unique is that we did take a mechanistic approach — we explored why this connection might exist.”

What the researchers found was that even common respiratory viruses that do not infect neurons can leave lasting changes to the nervous system.

In their animal models, Miller’s team observed that COVID-19 and flu infections triggered an inflammatory response from immune cells in the nervous system — a process called gliosis — that remained elevated in the spinal cord even after the virus had been cleared from the body. Gliosis, Ahmed notes, is already known to play an important role in ALS, but the findings suggest that an infection may amplify this process, helping to accelerate the disease.

Catalog of mitochondria across life’s family tree unearths unusual functions

A research consortium has generated the broadest look yet at the proteins that make up mitochondria, capturing the organelle’s diversity across multiple branches on the tree of complex life. With major contributions from Broad Institute scientists and its Proteomics Platform, the consortium generated and analyzed the mitochondrial proteomes of one plant and five single-celled pathogens that affect millions of people globally every year.

Their results reveal unexpected functions of the organelle, clues to its origin and role in the evolution of complex-celled organisms known as eukaryotes, and potential new drug targets for neglected tropical diseases.

The MitoCarta Tree of Life project was led by scientists at the Broad Institute, Mass General Brigham, Harvard Medical School (HMS), Harvard T.H. Chan School of Public Health, and Boston University Henry M. Goldman School of Dental Medicine. Their findings appear in nine scientific papers and a commentary article in Cell and related journals.

New center boosts nuclear isotope output for deep-space missions

Canada is moving to expand its role in supplying nuclear isotopes that could power spacecraft on long-duration missions.

The Nuclear Innovation Institute launched the Canadian Centre for Space Isotopes this week in Toronto. The organization will focus on research, policy, and partnerships across the nuclear and space industries.

Radioisotope power systems convert heat from radioactive decay into electricity. They provide steady power without relying on sunlight, making them useful for missions traveling far from the Sun.

NASA’s Roman Space Telescope Takes First Coronagraph Instrument Observation

On September 22, the Coronagraph Instrument on NASA’s Nancy Grace Roman Space Telescope opened its eyes to cosmic light for the first time. The ultimate purpose of the instrument—which is commanded from Caltech’s IPAC, a science and data center for astrophysics and planetary sciences—is to demonstrate technology that can block starlight, providing unprecedented views of the planets and dusty disks around nearby stars.

The coronagraph first woke up on September 1 and stretched its digital, electronic, and mechanical “limbs” mid-month. Once the Roman team confirmed that the fine-guidance system was holding the Coronagraph Instrument steady, scientists adjusted the focus so it could take its first bleary-eyed look at space, which will help scientists fine-tune the instrument’s view.

“We’re all extremely pleased with how well things are working,” says Alexandra Greenbaum, coronagraph data management system lead at IPAC. “There’s a lot of collaboration that went into this milestone, so it’s wonderful to see all of us working together and to be a part of the team. I’m really looking forward to supporting the rest of commissioning, both on the operations and the data processing.”

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