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Upcoming Seminars

14th AISLO Meeting

TIGEM will host the 14th Edition of the AISLO (Associazione Italiana Sindrome di Lowe) Meeting.
When Jun 30, 2017
from 09:00 AM to 04:30 PM
Contact Name
Contact Phone 08119230620
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Speakers will be:

Antonella De Matteis, Biologia Cellulare, TIGEM 

Olivier Devuyst, Istituto di Fisiologia, Università di Zurigo 

Francesco Emma, Nefrologia, Ospedale Bambin Gesù, Roma 

Milena Cau, Genetica Medica, Università di Cagliari 

Claudio La Scola, Nefrologia pediatrica, Ospedale Sant’Orsola, Bologna 

Massimiliano Serafino, Oftalmologia Pediatrica, Ospedale San Giuseppe, Milano 

Mario Loi, Neuropsichiatria infantile, Cagliari

Patrizia Folegani, Neuropsichiatria infantile, ASL Ferrara

Michela Sesta, Neurologia Pediatrica, Ospedale Pediatrico Giovanni XXIII, Bari

Nicola Pietrafusa, Neurologia, Ospedale Bambin Gesù, Roma

Pietro Genovese, Ph.D. - "Towards Clinical Translation of Safe and Effective Hematopoietic Stem Cell Gene Editing for the Correction of SCID-X1 "

Gene transfer technologies and new gene therapy strategies, Unit San Raffaele -Telethon Institute for Gene Therapy (SR-TIGET) San Raffaele Scientific Institute IRCCS, Ospedale San Raffaele, Milano
When Jul 04, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Short CV

Abstract
The scope of genetic engineering of hematopoietic stem/progenitor cells (HSPC) has broadened from gene replacement to genome editing using artificial nucleases, enabling precise modification of endogenous genes. We exploited this strategy on HSPC to insert a functional cDNA into IL2RG gene, whose mutations cause SCID-X1, thus restoring its function and physiologic expression while avoiding the risk of insertional mutagenesis. To support the rationale and explore the safety of gene correction we developed a mouse model carrying a mutated IL2RG gene in place of Il2rg. To evaluate efficacy and safety of hematopoietic reconstitution from a limited number of corrected HSPC we performed competitive transplant with WT and IL2RG-/- HSPC and found that 10% of WT cells fully reconstitute the lymphoid compartments and that administration of a conditioning regimen before HSPC infusion is required to protect from the risk of lymphoma development from the transplanted progenitors. To validate the gene correction strategy in the disease model we developed a gene editing protocol based on CRISPR/Cas9 on murine IL2RG-/- HSPC. Upon transplant, the gene corrected cells were able to generate functional B and T lymphoid lineages, showing a clear selective advantage over uncorrected cells. The corrected cells persisted long-term in the mice and generated a functional T cell response upon in vivo challenge with a pathogen, indicating that IL2RG edited cells are able to partially correct the disease phenotype. Furthermore, by optimizing the gene editing protocol for human HSPC we could attain the threshold of IL2RG editing required for safe and effective disease rescue. By combining donor DNA delivery by AAV6 and advanced generation ZFNs we measured ~35% HDR in the bulk treated CD34+ cells and ~13% HDR upon transplant in NSG mice. Deep sequencing performed on treated CD34+ proved the high specificity of our optimized ZFNs, with no significant modification at any of the off-target sites identified by GUIDE-Seq for earlier generation ZFNs. Finally, to establish a clinical ready protocol, we scaled up the process, treating up to 25 million cells with highly qualified reagents. These studies established safety and robustness of HSPC gene editing for SCID-X1 and will be instrumental for the design of the protocol for its first clinical testing.


Simone Cenci, MD - “Autophagy in plasma cell pathophysiology”

Head, Age Related Diseases, San Raffaele Scientific Institute, & Università Vita-Salute San Raffaele, Milan, Italy
When Jul 11, 2017
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Short CV

Abstarct
Aging progressively impairs immune functions, including serological memory, a unique property of adaptive immunity afforded by bone marrow (BM) long-lived plasma cells (PCs) residing in dedicated, poorly understood niches. Aging reduces BM PCs and predisposes them to transform in the incurable cancer multiple myeloma (MM). The intrinsic and environmental mechanisms that maintain a healthy PC niche and how aging compromises them are elusive. Autophagy, a key proteostatic asset, opposes senescence, but is weakened by aging. Following our discovery that autophagy is essential to maintain BM PCs, we devoted efforts to investigate the underlying mechanisms and its role in MM. Our work reveals an unanticipated control linking autophagy to PC differentiation; discloses new levels of integration between protein homeostasis and other cellular functions; and identifies putative BM environmental circuits co-opted by MM development.

 

Ayelet Erez, M.D., Ph.D. - "The role of aminoacids' metabolism in carcinogenesis"

Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
When Jul 18, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Short CV

Abstract
The urea cycle (UC) functions in the liver to convert toxic ammonia and nitrogen waste to urea. Clinically, patients with urea cycle disorders present mostly with hyperammonemia leading to acute and chronic neurological abnormalities.  Surprisingly, in contrast to the established role of the urea cycle enzymes in ureagenesis, the expression of most urea cycle proteins is dysregulated in multiple cancers for which the benefit is unknown. We find that UC proteins' dysregulation in cancers generates a novel pattern of mutations which increases cancer survival, proliferation, invasion and migration and is hence associated with worsened patients' survival across cancers. Thus, our studies reveal oncogenic metabolic rewiring that maximizes the use of nitrogen by cancer cells and has prognostic and diagnostic values.

Robin Ali, Ph.D. - "Gene therapy for retinal degeneration: rods, cones and rod-like cones"

Professor of Human Molecular Genetics, Division of Molecular Therapy, UCL Institute of Ophthalmology, London, UK
When Jul 25, 2017
from 12:00 PM to 01:30 PM
Contact Name
Contact Phone 081-19230659
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Amit Nathwani, M.D. - Department of Haematology, University College London Cancer Institute, London, UK

When Sep 12, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Ido Amit, Ph.D. - "The power of ONE: Immunology in the age of single cell genomics"

Immunology Department , Weizmann Institute of Science, Rehovot, Israel
When Dec 19, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Short CV

Abstract
The power of ONE: Immunology in the age of single cell genomics Ido Amit Weizmann Institute of Science Immune cell functional diversity is critical for the generation of the different regulator and effector responses required to safeguard the host against a broad range of threats such as pathogens and cancer, but also from attacking its own healthy cells and tissues
In multi cellular organisms, dedicated regulatory circuits control cell-type diversity and responses.
The crosstalk and redundancies within these circuits and substantial cellular plasticity and heterogeneity pose a major research challenge.
Over the past few years, we have developed a collection of innovative single-cell technologies, which provide unprecedented opportunities to draw a more accurate picture of the various cell types and underlying regulatory circuits, including basic mechanisms, transitions from normal to disease states and response to therapies. I will discuss some of our discoveries and how they change the current dogma in immune regulation as well novel technologies that combine single cell RNA-seq with CRISPR pooled screens and demonstrate the power of these approach es to probe and infer the wiring of mammalian circuits, fundamental to future engineering of immune cells towards desired responses, including immunotherapy