Daniela Weiskopf, Ph.D.

Predicting patient responses to cancer immunotherapy

FUNDED: FEBRUARY 2018

FUNDED BY: The generosity of LJI Board Member François Ferré and Magda Marquet

What was the goal of your SPARK project?

Dengue virus (DENV) is the most significant mosquito-borne viral disease in humans. The virus, which actually has four serotypes or strains (DENV1-4), causes a wide spectrum of clinical disease ranging from asymptomatic infection, undifferentiated fever, to dengue fever and dengue hemorrhagic fever (DHF). Currently there is no vaccine or specific treatment available to prevent or treat dengue, which poses a serious risk since as many as 400 million dengue infections occur worldwide annually, of which 96 million manifest clinically. The most serious reaction to dengue, DHF, occurs in a minority of patients and is characterized by bleeding and plasma leakage. Plasma leakage may lead to shock and can result in death if not managed appropriately in a timely fashion. Treatment is largely supportive in nature and relies on diagnosis by a highly trained physician. Interestingly, only a minority of patients will actually progress to severe dengue but currently physicians are unable to identify those patients reliably, requiring careful attention to fluid management and proactive treatment of hemorrhage of most patients. To be able to predict plasma leakage on the basis of a simple blood test is thus a key issue in the study and management of dengue fever. My SPARK project aimed to collect preliminary data to support the development of a diagnostic test that can predict disease severity in dengue patients.

SPARK project results:

For my SPARK project, I studied blood samples from dengue patients with different disease severity outcomes and defined transcriptional profiles of genes that are up- or down-regulated in these individuals. Interestingly, we identified a panel of genes that clearly predicted the development of bleeding and plasma leakage in this patient subset. We are now in the process to further validate these genes in more detail in an independent study cohort as well as develop a diagnostic test based on establishing short DNA segments, so called primers, that can be used to amplify these genes of interest in basic clinical settings. This diagnostic test to assess genes associated with disease progression to plasma leakage has the potential to identify patients at risk for severe disease and will be invaluable in the management of dengue virus infection and associated clinical disease. Our findings are expected to make an important, innovative, and original contribution to advancing solutions relevant to military and public health and ultimately lead to an improved outcome for the general public.

What’s next for this project?

I used the preliminary data that I was able to obtain thanks to my SPARK award to submit an independent proposal “Cellular and transcriptional immunosignatures to predict development of plasma leakage in acute dengue infection” to the Accelerating Innovation in Military Medicine (AIMM) mechanism of the Department of Defense. Although it was favorably reviewed and received an excellent score, it was unfortunately not recommended for further funding. We used that feedback to amend the application, including adding new additional data from the independent cohort, which yielded inconclusive results after repeated sequencing. Currently, we are sequencing the third cohort as a “tie breaker”. The amended application was resubmitted as an R21 application to the National Institutes of Health. Though the proposal was not chosen for funding, this was an invaluable experience for my career and professional development. These experiences have inspired continued grant applications and have reaffirmed my dream of having my own laboratory one day.