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Upcoming Seminars

Andrea Elena Dardis, PhD - "The common c.-32-13T>G splicing variant of GAA gene: from functional characterization to the development of new therapies for Pompe disease"

Head of the Laboratory of the Regional Coordinator Centre for Rare Diseases, Udine, Italy
When Jan 22, 2019
from 11:30 AM to 12:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Abstract
Pompe disease (PD), is an autosomal recessive lysosomal storage disorder due to mutations in the GAA gene, which cause a functional deficiency of the alpha-glucosidase enzyme (GAA) and result in impaired glycogen degradation and accumulation within the lysosomes. Clinically, PD encompasses a continuous spectrum of phenotypes, ranging from infantile to late onset (LO) forms. Currently, the only approved treatment for PD is enzyme replacement therapy (ERT) with human recombinant GAA, which does not completely prevent disease progression.
The mutation profile of the GAA gene is heterogeneous; however, most patients affected by the LO phenotype carry the splicing mutation c.-32-13T>G in at least one allele, making this mutation an interesting target for therapeutic development. 
Therefore, we first performed an in deep functional characterization of this variant showing that it affects the binding of the U2AF65 splicing factor to the polypyrimidine tract of exon 2, leading to a complete or partial exclusion of this exon from the mature GAA mRNA. However, in the presence of this mutation, variable levels of the normal spliced GAA transcript and protein are produced.
Then, using a series of overlapping deletion constructs we mapped several splicing silencers within the exon 2 sequence and designed different antisense morpholino oligonucleotides (AMOs) to target those regions.  Using a minigene approach and patients fibroblasts we were able to successfully increase the inclusion of exon 2 into the mRNA and improve GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, treatment of patient myotubes with the AMOs combination resulted in a partial clearance of glycogen accumulation. These data suggest that in patients carrying the c.-32-13T>G mutation and retaining a substantial residual GAA activity, the AMOs effect on GAA might be enough to achieve a beneficial effect in clinical settings. These are very encouraging results and further studies will be directed to test the efficacy and the delivery of these AMOs to skeletal muscle in vivo.
An alternative promising approach to restore normal splicing of mutated transcripts is the use of small molecules that modify splicing patterns. We have developed a fluorescent reporter system suitable for highthroughput screening of molecules able to restore normal splicing of c.-32-13T>G mutant alleles. Using this approach we have screened a library of 1270 FDA approved compounds identifying several molecules able to partially rescue normal splicing.
In conclusion, our work has provided the bases for the clinical development of RNA based therapies and drug repurposing for the treatment PD patients carrying the c.-32-13T>G mutation. These therapeutic approaches alone or in combination with ERT, could improve the clinical outcome of this group of patients. 

Graziano Martello, PhD - "Pluripotent stem cells: from basic biology to disease modelling"

Associate Professor of Histology, DTI Telethon Scientist, Dept. of Molecular Medicine, University of Padova, Padova, Italy
When Feb 05, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Abstract
Pluripotent stem cells, such as Embryonic Stem (ES) cells or iPS cells have the capacity to form all cell types found in the adult organism. This capacity makes them an interesting biological phenomenon to study as well as a formidable tool for in vitro studies.
For these reasons my laboratory is interested in the mechanisms regulating the generation, maintenance and differentiation of pluripotent stem cells, as well as their use as an in vitro model of diseases.
Huntington Disease (HD) is an incurable neurodegenerative disorder caused by abnormal CAG expansion in the Huntingtin gene. I will share unpublished findings about the generation of a of HD in murine ES cells that was used for an unbiased genome-wide screening. Such screening allowed the identification of genes able to suppress the cytotoxic effects caused by mutant Huntingtin. We further validated and characterised some of the suppressors both in vitro and in an vivo model of HD that we developed in Zebrafish. Our results indicate that mutant Huntingtin affects several cellular processes among which the homeostasis of metals appears as a potential target for therapeutic intervention.

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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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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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.