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Upcoming Seminars

Flavia Valtorta, M.D., Ph.D. - "PRRT2: from synaptic vesicle exocytosis and actin dynamics to paroxysmal neurological disorders"

Division of Neuroscience, San Raffaele Scientific Institute, Milan
When Jun 26, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
In the past few years proline-rich transmembrane protein 2 (PRRT2) has been identified as the causative gene for several paroxysmal neurological disorders. Mutations in PRRT2 are a major cause of paroxysmal kinesigenic dyskinesia, benign infantile familial seizures and infantile seizures with choreoathetosis. Mutations in the gene are responsible also for a minor fraction of cases of other neurological disorders, such as hemiplegic migraine and episodic ataxia, which share the feature of being paroxysmal disorders.

An important role of PRRT2 in synapse development and function is emerging. PRRT2 regulates neurotransmitter release by conferring Ca2+ sensitivity to synaptic vesicle exocytosis. In addition, it orchestrates synapse formation and maturation. Loss of PRRT2 renders neuronal networks unstable, thus predisposing to paroxysmal phenomena.

The study of PRRT2 and of its mutations may help in refining our knowledge of the process of synaptic transmission and elucidating the pathogenic mechanisms leading to derangement of network function in paroxysmal disorders.

Thomas Meitinger, MSc, MD

Director, Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München and Director, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg
When Jun 27, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Stefano Biffo, Ph.D. - "Translational control of metabolism"

Professor of Cell Biology and Comparative Anatomy, University of Milano & Program Leader INGM "Romeo ed Enrica Invernizzi", Milan, Italy
When Jul 03, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Nutrients are known to coregulate protein synthesis and metabolism through activation of mTOR kinase. However, whether translation can itself act upstream of metabolism is unknown. In this talk, we explore the mechanisms by which translation factors control lipid metabolism at the translational level, generating a feed-forward loop that enforces metabolic remodelling toward an anabolic phenotype. The relevance of these mechanisms in normal physiological T cell response, and cancer and metablic syndromes will be demonstrated.

Pasqualina Colella, Ph.D. - "Developing improved AAV gene therapy approaches for Pompe disease"

Immunology and Liver gene therapy, Genethon, Evry, France
When Jul 10, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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In vivo gene therapy with adeno-associated-virus (AAV) vectors has recently shown to provide persistent therapeutic efficacy in several human inherited diseases, upon a single administration. This result, together with the marketing approval of the first AAV-based drugs, has the potential to change the standard of care of many human genetic diseases. Yet, the development of efficient AAV-based strategies is crucial to reach the therapeutic threshold in diseases requiring high/widespread transgene expression and/or transgene persistence during growth. The improvement of AAV gene therapy approaches is relevant especially considering that vector doses administered in humans correlate not only with efficacy but also with potentially detrimental immune responses. Finally, avoiding immune responses against therapeutic transgene products is key to the success of all AAV gene therapies. Based on these considerations, I will present the work we have done in the past years to develop improved AAV gene therapy strategies for the effective treatment of pediatric diseases requiring multi-organ targeting and the induction of immune tolerance to the therapeutic transgene product. To validate the improved AAV strategies we used Pompe disease (PD) as prototype disease model and provided proof-of-concept of efficacy in the PD mouse and in non-human primates. PD is caused by the lack the ubiquitous enzyme acid-alpha-glucosidase (GAA) and presents with multi-organ manifestations and frequent anti-GAA immunity that hampers the efficacy of enzyme replacement therapy (ERT). PD shows signs of both lysosomal storage disease and neuromuscular disease and its effective treatment would require the restoration of GAA activity virtually whole-body. In our studies, we found that the rational design of both transgene and regulatory elements allowed the development of improved AAV-GAA vectors. This allowed to restore GAA activity in multiple affected tissues long-term and to provide sustained immune tolerance to the transgene product. Interestingly, using improved AAV-GAA vectors, we observed whole-body therapeutic efficacy at low vector doses. Notably, this approach could potentially be translated to other diseases sharing similar therapeutic needs.