A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment.

Adeno-associated virus (AAV) gene therapies are generating much excitement in the rare disease field, particularly for previously untreatable neurological conditions. Efficacy has been claimed for several gene therapy products and the number of trials is rapidly increasing. However, reports of severe treatment-related adverse reactions are emerging, including death. There is still insufficient knowledge about their aetiology, prevention and treatment. We therefore undertook to systematically review publicly available data on AAV gene therapies in order to collate existing information on both safety and efficacy. Here, we review emerging efficacy reports of these novel therapies, many of which show promise. We also collate an increasing number of adverse reactions. Overwhelmingly, these results make a case for unified reporting of adverse events. This is likely to be critical for improving the safety of these promising treatments.

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.

The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage-associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.

Autophagy Driven Extracellular Vesicles in the Leukaemic Microenvironment.

The leukaemias are a heterogeneous group of blood cancers, which together, caused 310,000 deaths in 2016. Despite significant research into their biology and therapeutics, leukaemia is predicted to account for an increased 470,000 deaths in 2040. Many subtypes remain without targeted therapy, and therefore the mainstay of treatment remains generic cytotoxic drugs with bone marrow transplant the sole definitive option. In this review, we will focus on cellular mechanisms which have the potential for therapeutic exploitation to specifically target and treat this devastating disease. We will bring together the disciplines of autophagy and extracellular vesicles, exploring how the dysregulation of these mechanisms can lead to changes in the leukaemic microenvironment and the subsequent propagation of disease. The dual effect of these mechanisms in the disease microenvironment is not limited to leukaemia; therefore, we briefly explore their role in autoimmunity, inflammation and degenerative disease.

ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection.

Hematopoietic stem cells (HSCs) undergo rapid expansion in response to stress stimuli. Here we investigate the bioenergetic processes which facilitate the HSC expansion in response to infection. We find that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation. The initial increase in mitochondrial mass occurs as a result of mitochondrial transfer from the bone marrow stromal cells (BMSCs) to HSCs through a reactive oxygen species (ROS)-dependent mechanism. Mechanistically, ROS-induced oxidative stress regulates the opening of connexin channels in a system mediated by phosphoinositide 3-kinase (PI3K) activation, which allows the mitochondria to transfer from BMSCs into HSCs. Moreover, mitochondria transfer from BMSCs into HSCs, in the response to bacterial infection, occurs before the HSCs activate their own transcriptional program for mitochondrial biogenesis. Our discovery demonstrates that mitochondrial transfer from the bone marrow microenvironment to HSCs is an early physiologic event in the mammalian response to acute bacterial infection and results in bioenergetic changes which underpin emergency granulopoiesis.

CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma.

Metabolic adjustments are necessary for the initiation, proliferation, and spread of cancer cells. Although mitochondria have been shown to move to cancer cells from their microenvironment, the metabolic consequences of this phenomenon have yet to be fully elucidated. Here, we report that multiple myeloma cells use mitochondrial-based metabolism as well as glycolysis when located within the bone marrow microenvironment. The reliance of multiple myeloma cells on oxidative phosphorylation was caused by intercellular mitochondrial transfer to multiple myeloma cells from neighboring nonmalignant bone marrow stromal cells. This mitochondrial transfer occurred through tumor-derived tunneling nanotubes (TNT). Moreover, shRNA-mediated knockdown of CD38 inhibits mitochondrial transfer and TNT formation in vitro and blocks mitochondrial transfer and improves animal survival in vivo. This study describes a potential treatment strategy to inhibit mitochondrial transfer for clinical benefit and scientifically expands the understanding of the functional effects of mitochondrial transfer on tumor metabolism. SIGNIFICANCE: Multiple myeloma relies on both oxidative phosphorylation and glycolysis following acquisition of mitochondria from its bone marrow microenvironment.See related commentary by Boise and Shanmugam, p. 2102.