In 2017 Cincinnati Children’s Hospital investigator, Dr. Manoj Pandey, PhD., was awarded Center for Clinical and Translational Science Just In Time (CCTST-JIT) funding for the project, “C5a-C5aR1 function for brain storage of glucosylceramide in Gaucher disease”.  The goal of this study was to investigate if the protein complement 5a (C5a) interaction with its receptor (C5aR1) triggers the excess brain accumulation of the fatty molecule, glucosylceramide (GC), which sparks inflammation and can lead to neurodegeneration in Gaucher Disease. 

Gaucher disease is a rare disease, with an incidence of about 1 in 60,000 in the general population. Worldwide there are about 4,000 Gaucher disease patients. Certain therapies, such as enzyme replacement therapy and substrate reduction therapy, treat many of the visceral aspects of Gaucher disease but demonstrate diminished or no response in the brain and for which there is not an effective therapy. The results obtained from the JIT funded study provide new insights that might prove useful to design novel adjunctive therapeutic approaches that may apply to manage disease complications in patients with Gaucher’s, Parkinson’s and other lysosomal storage diseases.

This JIT project has led to two publications, funding from the Michael J. Fox Foundation, and Media Coverage:

• Pandey M, Magnusen D, Mckay M, Magnusen A, Rani R, Caballero M, Zhang W, Setchell K, Grabowski G, Köhl J. Complement drives neurodegeneration in Gaucher disease. European Journal of Immunology 2017, 47(S2), 157-157.

• Pandey MK, Grabowski GA, Köhl J. An unexpected player in Gaucher disease: The multiple roles of complement in disease development. Semin Immunol 2018, S1044-5323(17)30104-5. (PMID: 29478824).

• To learn more about Dr. Pandey’s study funded Michael J. Fox Foundation, click here

• To view Media Coverage that Dr. Pandey has been featured in, click here

The mission of the CCTST-JIT grant mechanism is to enable investigators to use University of Cincinnati or Cincinnati Children’s Hospital Medical Center Core facilities to obtain critical data for submission of a competitive extramural proposal, patent application or commercialization agreement.  The JIT application cycle is open from September 9, 2019 - October 7 2019; click here for details.

CCHMC + Live Well Collaborative Projects Release New Publications

The Live Well Collaborative (LWC) is a nonprofit founded in 2007 by the University of Cincinnati (UC) and Procter and Gamble (P&G). LWC specializes in user-centered research that translates into the development of products, services and system solutions for living well across the lifespan. It is a unique academic-industry innovation center that leverages the vitality and unbiased innovation capability of multi-disciplinary teams of UC faculty and students. During the course of a 15-week semester, LWC uses a proven design thinking process to translate user centered research into innovative products and services. LWC has the ability to use a design thinking approach to translate user insights into comprehensive visualizations of future alternatives that are executable and economically feasible.

LWC’s partnership with Cincinnati Children’s Hospital Medical Center (CCHMC) began with an introduction to CCTST Director, Jim Heubi, MD. Dr. Heubi recommended LWC test their process and methodologies with CCTST Community Engagement Director, Lori Crosby, PsyD, and her team on the first CCHMC sponsored studio project. This project provided proof of capability of the LWC process and outcomes, as well as Dr. Crosby’s team integrating design thinking methodologies into their daily practices. The CCTST joined the LWC as a strategic member in 2013. As a next step it was identified that CCHMC principle investigators needed a funding mechanism to support their project work. As a result, the CCTST developed a “Design Thinking Award” for CCHMC PI’s that awards researchers $10,000 toward a studio project with LWC. More information on the Design Thinking Award can be found on CCTST’s website: https://cctst.uc.edu/funding/designthinking.

During the past six years LWC has partnered with CCHMC researchers on over 40 studio projects. A document of case studies was created to highlight this work. Over the years, these projects have led to dozens of significant outcomes and publications.  Most recently, four projects have been published in scientific journals, and three manuscripts are under review. 

Recent Publications:

• Greiner MV, Beal SJ, Dexheimer JW, Divekar P, Patel V, Hall ES. Improving Information Sharing for Youth in Foster Care. Pediatrics, vol. 144, issue (2), August 2019.

• Henize AW, Beck AF, Klein MD, Morehous J, Kahn RS. Transformation of a Pediatric Primary Care Waiting Room: Creating a Bridge to Community Resources. Maternal and Child Health Journal, vol.22, no.3, June 2018, 779-785.

• Lane, B., Hanke, S., Giambra, B., Madsen, N., & Staveski, S. (n.d.). Development of a clinician–parent home care education intervention. Cardiology in the Young, 1-6.

• Victoria Hickey, Laura Flesch, Adam Lane, Ahna L.H. Pai, John Huber, Priscila Badia, Stella M. Davies, Christopher E. Dandoy. Token economy to improve adherence to activities of daily living. Pediatric Blood Cancer. 2018;65:e27387.

Additional Resources:

• CCHMC + Live Well Case Studies

• Overview of new publications from CCHMC + Live Well publications

References: Content from this story courtesy of CCHMC + Live Well Case Studies.

Story courtesy of University of Cincinnati, College of Medicine, Dean's List Weekly News

Brett Kissela, MD, CO-PI of the CCTST's Clinical and Translational Science Award (CTSA), Professor and Chair of Neurology and Rehabilitation Medicine and Senior Associate Dean for Clinical Research at University of Cincinnati, has been accepted into the 2019-2020 Class of the Association of American Medical Colleges (AAMC) Council of Deans Fellows. The fellowship program was created to enhance the development of future leaders in academic medicine. It is designed for senior faculty members, including department chairs and assistant and associate deans, who are interested in being considered for deanships in the future.

Through the program, Kissela will receive mentoring from current medical school deans, make two visits to the medical schools of dean mentors, participate in meetings of the AAMC Council of Deans and its administrative board to learn about the strategic goals and activities of the council and participate in the Executive Development Seminar for Deans. He also will complete a leadership project.

Genes are what make each person unique; they control our outward appearance and internal functions, such as how our bodies react and respond to medicine. Because of different genetic makeups, not all people respond to medications in the same way. When drugs are approved for market, it must first be proven that on average the medication and recommended dose is affective in most patients. But this means that there is still a portion of people who don’t experience the intended effects of the drug; they either have no response at all or have an adverse reaction. Sander Vinks, PharmD, PhD, CCTST (the effector arm of the University of Cincinnati CTSA hub) member and Director of the Division of Clinical Pharmacology at Cincinnati Children’s Hospital Medical Center (CCHMC) explains, “as clinicians, we treat individual patients and we know that there are a lot of variables, not only in how patients handle drugs but also how they respond to them.”

Precision Medicine paired with Pharmacogenetics has the power to address this issue. According to the NIH National Library of Medicine, Precision Medicine is a quickly advancing medical approach for individualized disease treatment and prevention that focuses on a person’s genetic, environmental, and lifestyle factors. Pharmacogenetics focuses on the way genes respond to drugs. Also at play is Pharmacokinetics (PK), which is what the body does to the drug, and Pharmacodynamics (PD), which is the drug effect, or what the drug does to the body (Figure 1). Understanding this information, combined with knowledge of the patient’s genetic makeup, can therefore help clinicians prescribe the right medicine at the right dose.

An additional pharmacological challenge is that little research has been published on the dosing and safety of medications used to treat neonates, or newborn children. Dosing for neonates typically scales adult and pediatric pharmacological data to estimate a dosage that may be more appropriate for a newborn, but this can also lead to ineffective or unsafe dosing (Euteneuer JC, et al). Issues such as this led Dr. Vinks and a team of colleagues at CCHMC to develop the translational pain management tool, NeoRelief.

Using pharmacogenetics with a model-based PK/PD algorithm, NeoRelief was developed. NeoRelief is a decision support platform, embedded into electronic health records (EHRs), with the ability to predict and control precision dosing of morphine in real time for newborns in the neonatal intensive care unit (NICU). The goal of the platform is to help clinicians recognize the importance of optimal dosing and the impact of morphine on a patient’s response to pain. The team envisioned that NeoRelief would provide a real-time comparison of pain scores with the medication dosage and how the patient’s body interacted with the morphine. To achieve this vision and make these complicated elements more actionable, the team worked with a local business to create a dashboard that translates the comparisons into a clear readout, which includes heart rate, blood pressure, morphine dose, predicted concentration, and pain scores. NeoRelief can now bring all this information to the bedside to assist with medical actions and decision making.

The NeoRelief tool was developed by a multidisciplinary team of experts from CCHMC, including individuals from Neonatology, Clinical Pharmacology, Pharmacy, Medical Informatics, Information Services, Innovation Ventures, and the consulting firm, Medimatics. This project was initially funded by the CCTST Pilot Translational and Clinical Studies Program (previously known as T1) in 2014. Additional funding from the CCHMC Innovation Fund and the Peri-Natal Pilot Fund was acquired to build NeoRelief, and funding from the Gerber Foundation is being used to prospectively evaluate its impact. NeoRelief now has state funding to move to the next level into commercialization.

Using the same precision dosing model that guided NeoRelief, additional tools, applications, and wearables are being developed for the measurement and precision dosing of other medications. Dr. Vinks and his team are working with regulatory officials to make model-informed precision dosing a common clinical practice.

For more information on the precision dosing model, visit CCHMC Stream to watch Dr. Vinks Pediatric Grand Rounds presentation, “Personalized Medicine through Model-informed Precision Dosing: What’s Here – What’s Near?”, or review the publication, “Suggestions for Model-Informed Precision Dosing to Optimizing Neonatal Drug Therapy”.

References:

Euteneuer JC, Kamatkar S, Fukuda T, Vinks AA, Akinbi HT. Suggestions for Model-Informed Precision Dosing to Optimize Neonatal Drug Therapy. The Journal of Clinical Pharmacology. 2018;59(2):168-176. doi:10.1002/jcph.1315.

Vinks, AA. Personalized Medicine through Model-informed Precision Dosing: What’s Here – What’s Near. CCHMC Stream. 2018.

What is precision medicine? - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/primer/precisionmedicine/definition. Published April 30, 2019. Accessed May 8, 2019.

The KL2 Research Scholars Mentored Career Development Award is offered to highly qualified junior faculty pursuing careers in clinical and translational research. The KL2 program provides mentorship, career development opportunities, and financial support for salary and research-related expenses for up to two consecutive years. During the award period, Scholars are expected to pursue their own K23 (or similar individual career development awards) or R01 grants. Also involved in the Program are CT2 Scholars, which have the same goals and requirements as the KL2 but have a different funding structure.

All 8 of the current KL2 and CT2 Scholars are doing exceptional work across the Academic Health Center. Below are a few recent Scholar highlights:

Scholar Highlight:

Aristide Merola, MD, PhD, Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, has been an appointed KL2 Scholar since 2017. Dr. Merola was recently involved in conducting a systematic review and meta-analysis to determine if the results of subthalamic deep brain stimulation (DBS) surgery vary among different forms of Parkinson’s disease. DBS is a therapy used to improve motor functions in patients with Parkinson’s disease. The project, titled, “Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease”, involved 518 patients from 17 published studies. The analysis found that the DBS treatment yielded similar results in motor function changes, but the dopaminergic doses, activities of daily living, motor complications, and cognitive function outcomes varied in patients with different gene mutations (LRRK2, GBA, or PRKN). The analysis was published in JAMA Network in February 2019; click here for more details.

Dr. Merola was also invited to present at the National German Meeting of Parkinson’s Disease in March 2019, where he spoke on, “Efficient Directional DBS Programming: Translating Directional DBS best programming practices in Clinical Studies to the Clinic with the InformityTM interface”.

ACTS Meeting:

The Association for Clinical and Translational Science (ACTS) hosts a national meeting each year in Washington D.C. with the mission of bringing together all of the disciplines involved in clinical and translational research, for the shared benefits of networking and education. Four CCTST KL2/CT2 Scholars presented at the 2019 meeting in March:

• Moises Huaman, MD, MSc, poster presentation: Mycobacterium bovis Bacille-Calmette-Guérin infection aggravates atherosclerosis

• Stephanie Merhar, MD, MS, poster presentation: Reduced structural and functional connectivity in infants with prenatal opioid exposure

• Timothy Phoenix, PhD, poster presentation: Brainstem In Utero Electroporation Models of Pediatric Diffuse Intrinsic Pontine Glioma

• Elizabeth Kramer, MD, PhD, platform and poster presentation: TGFbeta, Early Cytokine Dysregulation, and Airway Smooth Muscle Dysfunction in Cystic Fibrosis