Punzo Lab News

Michelle Cheng shows that inhibition of vascular endothelial growth factor (VEGF) in the retina can promote inflammation by increasing the expression of cell adehesion molecules that enhance extravasation of immune cells from the vasculature. In a paper published in Human Gene Therapy she shows that rAAV mediated expression of a VEGF drug causes retinal vasculitis.

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. Here we show that the metabolic changes we induced in photoreceptors to cause AMD to not require HK2-mediated aerobic glycolysis to cause AMD-like pathologies in mouse. The data suggest that changes in the glucose lactate exchange between the retinal-pigmented epithelium and the photoreceptors are not what causes AMD in humans.
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The main cause for blindness in the elderly worldwide is age-related macular degeneration (AMD). What causes AMD remains unknown. The high metabolic demands of photoreceptors are thought to contribute to disease pathogenesis, yet whether photoreceptor metabolism differs in individuals with AMD has not been determined. In this research article Michelle Cheng shows that photoreceptor metabolism does differ between diseased and non-diseased individuals. Mimicking the metabolic profile of diseased individuals in mouse resulted in the similar advanced pathologies as those that cause blindness in humans. A disease model with photoreceptors as a contributing factor explains also why AMD affects preferentially the macula; it is the region of highest photoreceptor density. The data opens new avenues to develop treatment paradigms that target photoreceptor metabolism in AMD. Based on her findings Michelle is now developing therapy for the human disease by targeting photoreceptor metabolims.

Using a Hexokinase-2 conditional allele Lolita Petit shows that loss of aerobic glycolysis in rods leads to a metabolic switch in rods whereby rods start to rely on oxidative phosphorylation, by increasing the number of their mitochondria. In contrast, cones appear to compensate by increased lactate uptake that is produced by rods. However, in the absence of this mechanism cones in metabolically stressed disease condition such as retinitis pigmentosa, where rods have died, depend on aerobic glycolysis. Consequently, loss of aerobic glycolysis in cones of retinitis pigmentosa mice accelerates cone death.

Aditya Venkatesh shows that loss of the cone-enriched caspase-7 does not affect secondary cone death in two retinitis pigmentosa mouse models. Since caspase-7 activation has been shown to occur with ER stress the data suggests that ER stress is not a contributing factor to cone death in retinitis pigmentosa.

The BrightFocus Foundation awarded Dr. Claudio Punzo and his collaborator, Dr. Rahul Kanadia, a grant for his research into the cause of Age-Related Macular Degeneration (AMD). The award spans a time window of 2 years and is intended to test the role of photoreceptors in causing AMD. Dr. punzo has proposed that metabolic changes in photoreceptors could be the undelying cause for AMD in humans.

The International Retinal Research Foundation (IRRF) highlights Marina's research on their 2016 Cover. The research shows that altering cell metabolism in rods and cones in a cell autonomouse manner inmproves photoreceptor survival in a model of age-related macular degeneration that lacks retinal pigmented epithelium (RPE) cells due to sodium iodate administration. Interetsingly, the model shows that rod survival does not affect cone survival when the RPE is missing. The report also introduces the Punzo Lab.

Lolita Petit et al., show how development of photoreceptor outer segments influence AAV infectivity of rods. The data indicates that rods and cones compete for AAV access. Furthermore, the data indicates that the presence of an outer segment for rods greatly increases AAV infectivity. Her work was featured on the cover, which shows a 3D-rendering of the outer nuclear layer 21 days post infection with AAV5-CMV-H2BGFP-IRES-Cre after subretinal injection at postnatal day 1 into the Ai9 tdTomato Cre-reporter line. Blue shows viral nuclear H2BGFP; green shows tdTomato expressions in transduced cells reporting viral Cre; red shows cones expressing cone arrestin and white shows nuclear DAPI. 

Erika Camacho, Claudio Punzo and Stephen Wirkus show with a mathematical model that cone death can be halted at any time during the disease progression by increasing nutrient availability to cones in a recent article entitled "Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model" and published in the Journal of Theoretical Biology.

Lolita Petit, Hemant Khanna, and Claudio Punzo, UMass Chan Medical School, Worcester, coauthored the article "Advances in Gene Therapy for Diseases of the Eye."

International Retinal Research Foundation (IRRF) Reporst on Marina's research.
"Age-related macular degeneration (AMD) is characterized by malfunction and loss of retinal-pigmented epithelium (RPE) cells."

Morningside Graduate School of Biomedical Sciences Class of 2016 speaker Aditya Venkatesh will reflect on his path to science when he takes the stage at the 43rd UMass Chan Medical School Commencement on Sunday, June 5. As a child growing up in India, he said he was fascinated by biology and dreamed of becoming a doctor.

Aditya and Claudio comment on their approach to significantly prolong cone survival in Retinitis Pigmentosa by activating mTORC1 in cones.

Gene therapy researchers at UMass Chan Medical School focused on degenerative retinal diseases are calling a promising new study out of the University of Oxford the “future” of gene therapy, after clinical trial participants with a rare eye disease experienced significant improvement in their vision.