This SBIR Phase II proposal is intended to further develop human ghrelin (hGhr) and human growth hormone (hGH) as a combination therapy for elderly patients with sepsis and septic shock. In the US, more than one million people develop sepsis every year, and nearly 80% of septic deaths occur in patients older than 65 years of age. Currently, no effective pharmacotherapy exists for the treatment of sepsis. One of the reasons for sepsis clinical trial failures is that the preclinical evaluation of anti-sepsis drug candidates has been conducted exclusively in young animals. Rat Ghr, for example, ameliorates sepsis in young, but not aged, rats. We have discovered that administration of GH upregulates the expression of the Ghr receptor and restores Ghr?s responsiveness in aged animals with sepsis. In our completed SBIR Phase I project, co-administration of hGhr and hGH (hGhr-hGH) significantly ameliorated sepsis-associated lung, liver, and kidney injury in septic aged animals. We further demonstrated that the combination therapy nearly doubled the survival rate of septic aged rats. Moreover, both hGhr and hGH have been clinically tested and used for other indications with an excellent safety profile. Based on our Phase I results, we hypothesize that hGhr-hGH can be further developed as an effective therapy for sepsis in the elderly. To advance hGhr-hGH therapy towards its clinical use against sepsis in the elderly, we plan to determine the combination therapy?s most effective dose and therapeutic window to attenuate tissue injury and improve survival. We will also study hGhr-hGH?s combination effects on safety and pharmacokinetics (PK). Finally, we will conduct an exploratory study in an ovine model of sepsis to evaluate hGhr-hGH?s effects on hemodynamic parameters and organ injury. These proposed studies should provide crucial information for the future filing of an IND application to further develop hGhr-hGH in clinical trials. Our ultimate goal is to obtain FDA approval for the use of hGhr-hGH as a safe and effective treatment for elderly patients with sepsis and septic shock.

Public Health Relevance

Sepsis is a major cause of death in the United States, but there is no effective FDA-approved treatment for sepsis. Attempts to treat sepsis have failed, in part, because new treatments are only tested in sepsis models with young animals, while most patients with sepsis are at least 65 years-old. We have shown that treatment with a combination of two human hormones (ghrelin and growth hormone) improves sepsis outcomes in aged animals. We plan to further develop this combination therapy toward its future approval by the FDA as a new treatment for elderly patients with sepsis and septic shock.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44AG046994-02
Application #
9199963
Study Section
Special Emphasis Panel (ZRG1-SBIB-G (11)B)
Program Officer
Fuldner, Rebecca A
Project Start
2014-06-15
Project End
2019-05-31
Budget Start
2016-09-15
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
$540,425
Indirect Cost
Name
Therasource, LLC
Department
Type
DUNS #
144994972
City
Roslyn
State
NY
Country
United States
Zip Code
11576