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Upcoming Seminars

Vania Broccoli, BSc, PhD - "Exploiting engineered synthetic AAV vectors for novel gene therapy strategies for infantile and age-related neurological disorders"

Director of Research CNR, Institute of Neuroscience and Head of the “Stem Cells and Neurogenesis” Unit, San Raffaele Scientific Institute, Milan
When Feb 26, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Abstract
The increased knowledge on the 3D architecture of the AAV capsid has enabled targeted modifications and engineering in order to change or enhance specific AAV properties. In a recent work a synthetic AAV9 variant, called PHP.eB, was selected with the unprecedented ability to cross the blood-brain barrier upon intravenous injection in adult mice and transduce simultaneously neurons, astrocytes and oligodendrocytes.
We have employed this variant to set-up a gene therapy approach to reverse Rett syndrome (RS) manifestations in mice. RTT is an orphan disease as has remained resistant to any therapeutic approach attempted so far. Majority of cases are caused by mutation in the X-linked gene MeCP2 which encodes for an epigenetic factor able to bind to CpG methylated nucleotides and stabilize gene repression. MeCP2 mutant mice recapitulates the severe pathology with strong locomotor deficits and premature death at around 9-10 weeks. MeCP2 loss leads to neuronal dysfunctions but not to overt neurodegeneration. In fact, MeCP2 gene re-activation at late phase of the disease can extensively rescue the disease manifestation in mutant mice. In addition, MeCP2 gene duplications are responsible for a neuroinfantile syndrome as severe as RS. Thus, we equipped the PHP.eB capsid with an instable MeCP2 transgenic cassette (iMeCP2). This design was defined to limit the overall viral MeCP2 transcript load and maintaining a strong control of the overall MeCP2 gene dosage. Systemic injections of PHP.eB-MeCP2 were able to rescue the motor, cognitive and molecular deficits normalizing the mutant mice and their lifespan. Gene expression analysis allowed us to identify an altered gene signature in mutant mice which was extensively reverted upon MeCP2 gene transfer. Some of the identified genes might represent new potential biomarkers of relevant clinical interest. With a similar strategy, we have established a gene therapy approach to restrain and block accumulation of alpha-synuclein toxic species that accumulate with time in Parkinson’s disease. Using a new synthetic AAV serotype, we enhanced the activity of the GCase lysosomal enzyme to stimulate the degradation of alpha-synuclein toxic species throughout the brain of a synucleopathy mouse model. By identifying the receptor for the intracellular uptake of exogenous GCase, we have been able to device a system to promote enzymatic cross-correction through a non-cell autonomous mechanism.    

 



Diana Passaro, PhD - "The bone marrow microenvironment in acute leukemia"

Research Associate, The Francis Crick Institute, London, UK
When Mar 05, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 08119230659
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Abstract
Acute leukemias are aggressive cancers developing both during childhood and adult life, with very poor overall prognosis. The main intervention line is standard high dose chemotherapy, an approach often associated with resistance/relapse as well as severe long-term side effects. The bone marrow (BM) niche and its role in supporting healthy and malignant haematopoiesis are receiving increasing attention over the last years. The BM is considered the “home” for several leukemias, which can perturb the homeostatic balance and lead to the dysregulation of the cross talk between the hematopoietic and stromal compartments. Understanding how leukemic cells remodel the niche for their own advantage is a crucial missing piece of the puzzle and represents an intriguing source of new targets. My work explores several aspects of the leukemia-microenvironment interaction in mouse models of the disease, patient-derived xenografts and 3D organoids. By using intravital two-photon imaging and high-throughput sequencing, I will describe the profound tissue alteration driven by acute myeloid leukemia.

Florian Sennlaub, MD, PhD - "How genetic-risk variants of age–related macular degeneration shape pathogenic inflammation"

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
When Apr 09, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Short CV

Abstract
CD47 activation by Thrombospondin 1 (TSP-1) is essential in maintaining the subretinal immunosuppressive environment and prevents the subretinal accumulation of macrophages. Age-related Macular Degeneration (AMD), a highly heritable, major cause of blindness, is characterized by the breakdown of the immune-suppression and an accumulation of pathogenic MPs. Of all genetic factors, a variant of Complement factor H (CFH) and a risk haplotype of 10q26 are associated with greatest linkage to AMD. We recently showed that complement factor H (CFH) and in particular the AMD-associated CFH variant, curbs Thrombospondin 1 (TSP-1) activation of CD47. We now demonstrate that monocytes from homozygous carriers of the major AMD-risk haplotype of the 10q26 locus significantly overexpress the High-Temperature Requirement A Serine Peptidase 1 (HTRA1). Mechanistically we demonstrate that HTRA1 hydrolyses TSP-1, preventing its ability to activate CD47 and induce MP elimination. Our study reveals a comprehensive mechanism how CFH and HTRA1 participate in the pathogenesis of AMD and opens new therapeutic avenues to restore subretinal immunosuppressivity and inhibit the pathogenic subretinal inflammation.

David Ron, MD - "Mechanisms that maintain protein folding homeostasis in the endoplasmic reticulum"

Professor of Cellular Pathophysiology and Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, England (UK)
When May 28, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Short CV

Abstract
A transcriptional and translational program that strives to match the complement of chaperones in the endoplasmic reticulum (ER) to the burden of unfolded proteins in the early secretory pathway (the Unfolded Protein Response or UPR) has long been known to exist and its functional importance has been showcased by genetic and pharmacological manipulations.
However, a homeostatic program centered solely on changes in the gene expression encounters an inherent latency imposed by the lag between changes in the internal milieu of the ER and rectifying changes in levels of UPR target mRNAs and proteins.
Here I will discuss how this problem might be resolved by post-translational adaptations that operate on a shorter time scale