Rose N. Gelineau-Morel, MD
Clinical Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Assistant Professor of Pediatrics, University of Kansas School of Medicine
Full Biography
Rose Gelineau-Morel, MD, Neurology, received a five-year, $819,494 K23 award from the National Institutes of Health – Eunice Kennedy Shriver National Institute of Child Health & Human Development for her project, “Pharmacogenomic Contribution to the Biotransformation of Trihexyphenidyl and Development of a Precision Dosing Model for Children with Dystonia and Cerebral Palsy”.
Pharmacogenomics is the study of how an individual’s genes affect an individual’s exposure to a drug, and biotransformation is the process of chemically altering a drug to make it easier to eliminate.
Cerebral palsy is a group of disorders affecting movement and posture. Dystonia in cerebral palsy causes involuntary muscle contractions, repetitive movements and abnormal posture.
“Dystonia in cerebral palsy affects about one in 1,000 children - a similar incidence to Parkinson’s disease in adults. Because of the involuntary muscle contractions, dystonia can make it difficult to participate in daily activities, move around, or communicate. It is very functionally disabling and significantly impacts quality of life, so we desperately need better treatments” said Dr. Gelineau-Morel.
There are currently no FDA-approved oral medications for pediatric dystonia and off-label treatments aren’t very effective and also have side effects. One such treatment is the medication trihexyphenidyl (THP). It is often prescribed for dystonia in children; however, many children have treatment-limiting side effects, such as dry mouth, urinary retention, and sedation or cognitive changes.
Dr. Gelineau-Morel’s earlier research of THP revealed that two distinct THP components (R-THP and S-THP) are metabolized differently and have different therapeutic efficacy. R-THP and S-THP are primarily broken down by CYP2D6 and CYP2C19, two special enzymes that have different levels of activity based on a person’s genetics. This means that an individual taking THP could have higher or lower levels of R-THP and S-THP in their body depending on their CYP2D6 and CYP2C19 genotype. By understanding more about how a person’s genetics impact their exposure to R-THP and S-THP, Dr. Gelineau-Morel will be able to develop more precise dosing recommendations for THP. With the help of the results, Dr. Gelineau-Morel will be able to create an individualized dosing plan to give the right amount of the medication to kids.
Dr. Gelineau-Morel’s K23 study has three aims:
- Determine the impact of CYP2D6 and CYP2C19 genotype on a child’s exposure to R-THP and S-THP.
- Develop a pediatric physiologically based pharmacokinetic model to simulate exposures to THP, R-THP, and S-THP based on child’s pharmacogenotype, age, weight, and sex.
- Establish the feasibility of a future exposure-controlled clinical trial of THP for dystonia in cerebral palsy.
Dr. Gelineau-Morel plans to use the results to apply for an NIH R01 grant for a clinical trial of THP. Furthermore, results from this study could support a new drug application for isolated R-THP, to maximize therapeutic benefits while minimizing adverse side effects of THP.
“We are really excited for this project to get started. Not only will this project help us use trihexyphenidyl to more effectively treat dystonia, but it will also support the development of a new drug for the treatment of dystonia that could be better than what is currently available. In the long-term, I hope to grow my research program in model-informed precision neurotherapeutics to identify the most effective treatments and doses for each child based on their cerebral palsy phenotype and genetics,” said Dr. Gelineau-Morel.
Dr. Gelineau-Morel’s primary mentor for the K23 grant is Dr. Steve Leeder. Study team members include Rachel Nass (Neurology), Megan Blaufuss (Occupational Therapy), Dr. Catherine Koertje (Precision Therapeutics), Dr. Andrea Gaedigk, Dr. Erin Boone, and Wendy Wang (Pharmacogenetics), Dr. Hung-Wen Yeh and Addison Leabo (Biostatistics), Dr. Paul Toren, Brandon Retke, and Dr. Bob Tessman (Analytical Chemistry).
This funding, award no. 1K23HD114899-01A1, covers a project period of January 1, 2025-December 31, 2029.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.