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Upcoming Seminars

Amit Nathwani, M.D. - "Haemophilia Gene Therapy"

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"
Contact Name
Contact Phone 081-19230659
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Abstract
Gene therapy for haemophilia A and B (factor VIII or factor IX deficiency respectively), the most common inherited bleeding disorders, offers the hope of a cure by facilitating continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the haemophilic patient’s own defective gene. Haemophilia may be considered a ‘low hanging fruit’ for gene therapy because a small increment in blood factor levels (>2% of normal) significantly ameliorates the bleeding diathesis from severe to moderate phenotype, eliminating most spontaneous bleeds. The first trial to provide clear evidence of efficacy after gene transfer in patients with haemophilia B was recently reported by our group. A single peripheral vein infusion of adeno-associated virus (AAV) vector containing the factor IX (FIX) gene led to dose dependent increase in plasma FIX at therapeutic levels with no persistent ill effects. The only toxicity observed was transient subclinical transaminitis at the high dose level, which resolved following corticosteroid treatment. FIX expression has remained stable in most patients for >6years permitting these patients to discontinuation of FIX prophylaxis without increasing the risk of spontaneous haemorrhage. We have not observed any late toxicities. In the last 5 years six new AAV-haemophilia B gene therapy trials have begun with the most promising data emerging from studies using the gain-of-function Padua mutation in the FIX gene. Two studies have report a 8-10-fold enhancement of FIX catalytic activity to approximate averages of around 30% of normal FIX values. Further advance are likely to emerge through engineering of capsids to improve the efficiency of AAV gene transfer to the human liver using substantially lower vector doses, thus further improving the safety profile of this vector. This should positively impact on safety and cost of goods.
Progress has also been made with haemophilia A, a more challenging target for gene therapy. Using our codon optimised AAV-FVIII expression cassette a BioMarin sponsored study recently showed Factor VIII expression of between 12-150% in 7 severe haemophilia A patients recruited to the high dose cohort. Other gene therapy trials in haemophilia A have commenced and should be reporting soon.
Therefore, rapid progress is being made in the field of haemophilia gene therapy. Attention has to now shift on vector production to improve efficiency, quality whilst reducing costs. These and other aspects of haemophilia gene therapy will be discussed.

Paolo Grumati, MD, Ph.D. - "How autophagy regulates endoplasmic reticulum turnover"

Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
When Sep 19, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230649
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The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of all its distinct domains. In mammalian cells the ER is degraded via selective autophagy pathway (ER-phagy) mediated by two specific receptors: FAM134B, responsible for ER sheets turnover and SEC62 that regulates ER recovery after stress. We identified reticulon 3 (RTN3) as a specific receptor for degradation of the ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger tubular ER fragmentation. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). The binding to LC3/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent from FAM134B. None of the other reticulon members has the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy of ER tubules.

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"
Contact Name
Contact Phone 081-19230659
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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