Biography:

Stanley Cohan is past Professor and Chairman, Department of Neurology, Georgetown University School of Medicine, the Founding Director of the Providence Multiple Sclerosis Center, Co-Founder of the Pacific Northwest Multiple Sclerosis Registry and Director of the Providence Neuroimmunology Translational Research Program. He has been an active multiple sclerosis clinical investigator since the early 1990’s. His primary interests are in the development of new therapeutic agents for the treatment of multiple sclerosis, mechanisms of multiple sclerosis pathogenesis and development of web and I cloud-based technology for multiple sclerosis patient monitoring and treatment.

Abstract:

The results of four clinical studies Multiple sclerosis is a leading cause of serious disability of young and middle-aged people in western nations. Natalizumab, a high efficacy medication for control of multiple sclerosis disease activity, increases risk of progressive multifocal leukoencephalopathy in patients harboring JC virus and may necessitate discontinuing natalizumab.  Because discontinuing natalizumab may increase the risk of multiple sclerosis reactivation by 30% or more, strategies to transition patients off natalizumab are needed. These reported studies purposes was to demonstrate that multiple sclerosis reactivation was related to duration of post-natalizumab drug-free washout interval, and by reducing washout duration, risk of multiple sclerosis reactivation could be significantly reduced. These studies employed  different methodologies and medications:  a retrospective analysis of  multiple sclerosis patients treated with dimethyl fumarate after discontinuing natalizumab, 2 prospective studies utilizing washouts of 6,  8, 12 and 16 weeks since last natalizumab before initiating fingolimod therapy, and lastly, 4 weeks since last natalizumab dose prior to initiation of teriflunomide. Results: There was 51% (p=0.0216) relapse risk reduction when starting dimethyl fumarate 90 days or less after the last natalizumab dose compared to waiting more than 90 days. Patients starting  fingolimod 8-12 weeks post-natalizumab had a lower risk of clinical disease activity than after  16 weeks washout, and compared to a washout of 6 weeks or less, patients with a washout of more than 8 weeks had an odds ratio of 6.8 (95% CI 1.4, 32.8) for return of disease activity.  Utilizing 4-week natalizumab washout, 94% patients remained relapse-free after one year of teriflunomide treatment (95% CI 0.83, 0.98). These studies, utilizing different medications and designs, each demonstrated that minimizing post natalizumab washout was associated with reduced multiple sclerosis reactivation and conform with anticipated results when considering the pharmacodynamics of natalizumab receptor desaturation, and efficacy onset time of these 3 different therapeutic agents.

Recent Publications

1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled tral of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899-910

2. Bloomgren G, Richman S, Hotermans C, et al. Risk of antalizumab-associated progressive mutifocal leukoencephalopathy. N Engl J Med 2012; 366:1870-1880

3. West TW, Cree BA. Natalizumab dosage suspension: are we helping or hurting? Ann Neurol 2010; 68:395-399

4. Cohan SL, Moses H, Calkwood J, et al. Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to dimethyl fumarate: A multicenter retrospective observational study. Mult Scler Relat Disord 2018; 22:27-34 

Biography:

Thierry Douki is a Senior Scientist interested in the genotoxic properties of several physical (UV radiation) and chemical agents (pollutants, warfare agents). Chemist by training, he is expert in the reactivity of DNA and uses HPLC-tandem mass spectrometry assays to quantify DNA damage in relevant cellular models. He is co-author of more than 250 articles and book chapters and is expert for the French Agency for Food, Environmental and Occupational Health & Safety (ANSES).

Abstract:

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants found in food and urban atmospheres and associated with numerous professional occupations. One major health effect of PAH is their carcinogenic properties which result mostly from their ability to damage the genome. While parent PAH are not reactive, their metabolites damage biomolecules and in particular DNA through the formation of covalent adducts. These processes are well described for individual PAH, in particular benzo[a]pyrene (B[a]P). The genotoxic effects of mixtures of PAH have been less studied. In the recent years, we investigated the effects of synthetic mixtures and environmental extracts on hepatocytes, lung cells and skin explants. Emphasis was placed on the induction of phase I CYP450 mono-oxygenase genes and the formation of B[a]P-diol-epoxide (BPDE) adducts to DNA. In most cases, we observed lack of additivity, either synergy or inhibition, even in simple binary mixtures. In addition, a same mixture did behave the same way in different models, with synergy being frequent in hepatocytes and inhibition in lung cells and skin. Surprisingly, no correlation could be found between the induction of CYP genes, which is always larger with mixtures than with pure B[a]P and the extent of DNA damage. The bulk of these observations are in agreement with other data of the literature and show that the toxicity equivalency factor approach currently used for the prediction of risk is not optimal. New tools based on more sophisticated modelization are necessary. 

Biography:

Whitney Shatz received her M.S. in Biochemistry and Molecular Biology from the University of California in Santa Barbara, characterizing bacterial enzymes involved in the epigenetic process of DNA methylation. Since 2007, she has worked within the research organization at Genentech, supporting production and characterization of large molecule biologics. During her 11-year tenure, she has made significant contributions to the investigation of structure activity/relationship in antibody-dependent cell cytotoxicity (ADCC), as well as to the advancement of novel bispecific antibodies in a variety of disease areas. More recently, her focus has shifted to the development and characterization of protein-polymer bioconjugates for long-acting drug delivery. In addition, since 2016 she has been concurrently pursuing a doctorate in Pharmaceutical Sciences at the University of Geneva.

Abstract:

Statement of the Problem: Age-related macular degeneration is an eye disease affecting the back of the eye which gradually destroys sharp central vision [1], and has the potential to greatly impact quality of life [2]. Intravitreal injection is the preferred route for ocular drug delivery of protein therapeutics, where maximal benefit is achieved with dosing every 4-8 weeks [3]. Less frequent dosing would reduce treatment burden and increase patient compliance [4], highlighting the need for long-acting delivery (LAD) technologies.

Methodology and Theoretical Orientation: Since clearance from the eye is governed primarily by diffusion [5], therapeutic Fab was chemically conjugated to various multivalent scaffolds via maleimide chemistry to increase Fab half-life. Each Fab-conjugate candidate was assessed based on a multitude of criterial including conjugation efficiency, ratio of Fab to carrier, hydrodynamic radius, long terms stability, viscosity and activity (Figure 1). In some cases, in vivo tolerability experiments were performed to assess biocompatibility with ocular tissues. Findings: Evaluation of each system revealed attributes desirable for ocular LAD. Scaffolds composed of either PEG, HPMA or lipoprotein were effective in increasing Fab R_H. Geometry did not greatly influence R_H but had an impact on  viscosity. Biocompatibility study demonstrated tolerability of PEG but not of lipoprotein carrier. Conclusion and Significance: Though R_H measurements in vitro are useful for predicting vitreal half-life [6], scaffold biocompatibility is more complicated and has remained a major hurdle to the success of novel technologies.