About This Project
Bone marrow transplantation is a promising therapy for blood cancers as it enables the replacement of a sick patient's hematological system with a healthy one. It is however often associated with the induction of graft-versus-host disease, a condition leading to death. As previously developed therapeutic strategies remaine greatly inefficient, the aim of this project is to identify new drugs capable of blocking the onset of graft-versus-host disease following bone marrow transplantation.
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What is the context of this research?
Bone marrow transplantation is a unique treatment for various types of blood cancers. However, inhibiting graft-versus-host disease is necessary to ensure the success of the therapy. If successful, our approach will lead to the development of a promising experimental therapy to overcome one of the most critical bone marrow transplantation-based complications. One must note however that currently, the most effective approach to prevent graft-versus-host disease consists of a combination regimen disrupting the disease activation. In line with this notion, our study may lead to the development of novel therapies to be used alone or in combination with other treatments. Such approach is more likely to improve or yield better results than a single monotherapy or currently used strategies.
What is the significance of this project?
Leukemia is one of the most common blood cancers, and administration of current treatments to these vulnerable patients can lead to additional life-threatening complications such as kidneys dysfunctions, seizures, fluid retention and increased blood sugar levels. We strongly believe that the proposed research project has the potential to identify candidate compounds capable of preventing graft-versus-host disease while displaying limited side effects (as the screened libraries contain previously FDA-approved off-patent drugs). If successfully validated, these compounds will pave the path for new avenues in graft-versus-host disease control and increase the percentage of remission among bone marrow transplantation-treated cancer patients.
What are the goals of the project?
To successfully perform high-throughput screening, one must develop an efficient fluorescent-based assay capable of delivering confident read-outs. Our assay is based on the use of cells capable of expressing the green fluorescent protein once activated in vitro (mimicking the autoreactive response observed during graft-versus-host disease). The green fluorescent protein intensity is directly proportional to the strength of signaling. As such, two days following co-cultures of activated cells with each of the 2000 off-patent compounds, the green fluorescent protein intensity will be analyzed using a robotic system. Generated raw values with low or no green fluorescent protein signal will be retained for a secondary screening to discard any false positives.
We have designed an in vitro fluorescent cell-based assay, which enables the assessment of cellular viability and/or proliferation using an automated screening process. The assay is reliable and highly reproducible (repeated multiple times with consistent results). However, the access to the chemical library currently available at the university requires 5 000$. This study will not only allows us to generate preliminary data in order to prepare and submit a research grant requesting over 100K in order to continue the completion of the project (secondary screen, molecular characterization of the compounds and in vivo testing), but it will also reposition an off-patent FDA approved drug for another indication (graft-versus-host disease in this case). Furthermore, the identified drug could easily be translated to clinical trials as all required toxicology and pharmacokinetics have been previously completed.
Meet the Team
Dr. Rafei is the principal investigator on this project. With over 10 years of accumulated expertise in the fields of T cells and cytokine biology, Dr. Rafei will dedicate 20% of his time and efforts to guide the overall scientific and operational management. An MSc candidate will constitute the core personnel of this proposal. He will dedicate 100% of his efforts to complete this project.
I am an expert in cellular and molecular immunology with immunotherapeutics, cell therapy and lymphocyte biology focus. People consider me as an innovative scientist continuously proposing and implementing new therapeutic strategies while fostering external collaborations based on emerging human disease understanding. I have the ability to work comfortably under pressure while maintaining high energy level in a field that emphasizes speed, organizational skills, decisiveness, and effective interpersonal communications. I have also gained a wide expertise in training laboratory personnel with consistent track record of surpassing standards and goals. I therefore intend to use the knowledge I acquired over the last 15 years to discover new drugs that will enable me to save the life of cancer patients awaiting to receive bone marrow transplantations.
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