Research Overview

The Center for Orphan Drug Research (CODR) works to improve the care of individuals suffering from rare diseases through research on new drug therapies; education of health professionals and health profession students; and contributions to the discussion and formulation of public policy relating to rare diseases and orphan drugs. The focus of CODR research is rare pediatric neurological disorders.

Help support our research on rare pediatric neurological disorders.

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Seizure Disorders

PK-PD of IV Allopregnalone in Dogs with Epilepsy

Project Synopsis

This project involves the use of dogs with epilepsy to characterize the pharmacokinetic and pharmacodynamic properties of approved and investigational antiseizure drugs (ASDs). The canine epilepsy model permits studies on the differential effects of ASDs on behavior, sleep, and EEG as well as the relationship between drug exposure (e.g. plasma drug concentrations) and effects such as changes in sleep or EEG patterns. Allopregnanolone is a naturally-occurring neurosteroid that is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. A Phase III clinical trial is evaluating allopregnanolone administered by continuous intravenous (IV) infusion as a treatment for super-refractory status epilepticus (SE) in patients under general anesthesia in an intensive care setting. We hypothesize that allopregnanolone possesses the requisite pharmacokinetic (PK) and pharmacodynamic properties to support its use as an initial IV or intramuscular (IM) bolus treatment for SE. Our study objectives are to assess the tolerability and develop a PK model of allopregnanolone following a 5 minute IV infusion and an IM injection, both clinically applicable regimens for the initial treatment of SE.

PIs: Greg Worrell, MD, PhD; James Cloyd, PharmD; Ned Patterson, DVM, PhD; Lisa Coles, PhD; Ilo Leppik, MD; Michael Rogawski, MD, PhD
Funding: NIH NINDS

Development of a Prodrug/Enzyme Nasal Spray for Rapid Delivery of Diazepam for Rapid Treatment of Seizure Emergencies

Project Synopsis

Seizure emergencies (SE) are seizure clusters or prolonged seizures lasting at least 5 minutes.  Rectal diazepam has been the mainstay of out-of-hospital SE management, but many older children and adults object to this therapy. Intranasal formulations potentially offer safe, effective, and more socially acceptable treatment options. However, first generation intranasal therapies have limitations such as suboptimal rates of absorption, variable bioavailability, and reliance on organic solvents. Our group has developed a novel intranasal drug delivery system involving a water-soluble diazepam prodrug that is mixed with a converting enzyme at the time of administration. Two doses with different quantities of prodrug/enzyme will be administered intranasally to each of two dogs with epilepsy, one with intracranial EEG electrodes. To determine the absolute bioavailability of the intranasal formulation, an IV dose of  0.5 mg/kg will also be administered at another time.  Blood samples will be collected through a 16-gauge, external, jugular central line catheter just prior to administration and serially up to 8 hours afterwards. Simultaneous with blood collections, EEG signals will be recorded. Drug concentrations will be measured using an LC/MS assay. Drug concentrations and EEG data will be used to determine the onset, magnitude, and duration of effect.

PI: Ron Siegel, ScD
Co-PI: Jim Cloyd, PharmD
Co-Investigators: Gunda Georg, PhD; Ilo Leppik, MD; Ned Patterson, DVM, PhD; Lisa Coles, PhD
Funding: University of Minnesota Committee for Pharmaceutical Development


Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx)

Project Synopsis

Epileptogenesis is common after traumatic brain injury (TBI)and begins early, offering a window of opportunity  to test the efficacy of potential antiepileptogenic therapies. In order to design economically feasible clinical trials of such therapies it will be necessary to identify reliable biomarkers that: 1) predict later Post traumatic Epilepsy (PTE), to enrich the subject population; 2) stage the epileptogenic process, to determine the timing of intervention; and 3) diagnose epilepsy, to provide surrogate markers of outcome. To date promising electrical, imaging, and other biomarkers of epileptogenesis after TBI in animal models, including patholgical high frequency oscillations (pHFO) and repetitive pathological high frequency oscillations (RpFHOs) have been identified. The primary aim of the study is to perform prospective multicenter combined scalp and depth cEEG monitoring in moderate-severe TBI patients to determine if the occurrence of specific EEG changes, such as seizures, pHFOs and RpHFOs, predict later PTE. Our aims are to evaluate using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate potential therapeutic agents to treat PTE.

coPIs:  Engel, Galanopoulou, Moshe, Solomon, Pitkanen, and Toga
UMN Investigators:  James Cloyd, Pharm.D.; Lisa Coles, Ph.D.
Funding: NIH/NINDS

Spasticity

Development of IV Baclofen for Prevention and Management of Baclofen Withdrawal Syndrome

Project Synopsis

This project is directed at developing a new therapy to treat the symptoms associated with acute withdrawal of baclofen, a drug used to treat spasticity. The acute withdrawal syndrome can occur when spinal cord infusion of baclofen by pump is interrupted due to pump dysfunction, catheter dislocation, or site infection or when oral baclofen is interrupted because of a patient’s inability to take medications by mouth. Fewer than 5,000 patients per year experience baclofen withdrawal syndrome.  In addition, there are circumstances when interruption of oral baclofen therapy is anticipated (such as elective major surgery), and substitution with intravenous medication would reduce the risk of developing withdrawal. 

Co-PIs: Robert Kriel, MD; Co-PI: Linda Krach, MD
Co-Investigators: James Cloyd, PharmD; Lisa Coles, PhD;
Funding: Allaysis, Inc
Project Coordinator:  Natalie Schmitz, PharmD

Oxidative Stress In Neurodegenerative Disorders

Lysosomal Disease Network

Project Synopsis

The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS.  This network focuses on observational and intervention studies of various lysosomal diseases.

PIs: Chester Whitley, PhD, MD; James Cloyd, PharmD
Co-investigators(Pharmacotherapy Core): Reena Kartha, PhD; Lisa Coles, PhD
Funding: Through a collaboration between NCATS, NINDS, and NIDDK

Intranasal naloxone for treatment of impaired awareness of hypoglycemia

Project Synopsis

Recurrent exposure to iatrogenic hypoglycemia in patients with insulin treated diabetes can lead to development of impaired awareness of hypoglycemia (IAH)Naloxone- an opiod receptor antagonist has been shown to modulate hormonal response during hypoglyceamia and may play a role in the treatment of impaired awareness of hypoglycemia (IAH).This is a single center, single blind randomized cross-over design trial to evaluate intranasal nalaxone therapy for prevention and treatment of IAH. Secondary objective of this project is to characterize naloxone pharmacokinetics following multiple administrations. A 4mg dose of Narcan (naloxone hydrochloride) intranasal spray will be administered every 8 hours in one day. The primary endpoint of the study will be the within person difference in epinephrine secretion during the morning episodes of hypoglycemia on days one and two under the two treatment conditions.

Investigators: Amir Moheet, M.D.; Elizabeth Seaquist, M.D.; Lisa Coles, PhD.; Lynn Elberly, Ph.D.
Funding: University Of Minnesota, Academic Health Center

Nervonic Acid - a Potential Therapy to Alleviate Disease Progression in Adrenoleukodystrophy

Project Synopsis

We are also investigating the potential benefit of nervonic acid, a monounsaturated fatty acid, which can competitively inhibit the elongation of long chain fatty acids to VLCFAs.  There is a critical need to identify new treatments for patients diagnosed with ALD.  The primary objective of this project is to determine the effects of nervonic acid as a therapy for ALD.   We have observed that nervonic acid can reduce VLCFAs in cell models of ALD.  Now we will determine its effect on lowering VLCFA in tissues and assess its ability to reduce demyelination in laboratory mouse models of ALD. Further we will also characterize the pharmacology of Captisol®-enabled nervonic acid and evaluate the brain uptake in these animals.

PI: Reena Kartha, PhD
Co-Investigators (UMN):  Troy Lund, MD, PhD; James Cloyd, PharmD; Lisa Coles, PhD
Co-Investigators (Johns Hopkins University): Gerald Raymond, MD, Paul Watkins, MD, PhD, Ann Moser, BS
Funding: NCATS, CyDex Pharmaceutical

Role of Oxidative Stress and Inflammation in Type 1 Gaucher Disease (GD1): Potential Use of Antioxidant/Anti-inflammatory Medications

Project Synopsis

The primary objective of this study is to characterize oxidative stress and inflammation in the blood and brain of individuals with GD1 and determine whether these factors can be altered with orally administered N-acetylcysteine (NAC). Additionally, correlations between peripheral (plasma or red blood cell) concentrations of NAC, cysteine, and glutathione with central (brain) glutathione levels will be evaluated in subjects with GD1.NAC and glutathione pharmacokinetics will also be characterized in this population with the intent to construct models linking pharmacokinetics with biomarker changes.
 
PIs: Reena Kartha, PhD; Co-PIs: James Cloyd, PharmD; Jeanine Jarnes, PharmD
Co-Investigators:  Chester Whitley, PhD, MD; Kyle Rudser, PhD, Gulin Oz, PhD, Paul Tuite, MD, Neal Weinreb, MD (University of Miami, FL)
Funding: NIH-Lysosomal Disease Network, Pfizer

Novel Inflammatory Biomarkers Complement 5a And Hepcidin in Patients with Gaucher Disease (GD)

Project Synopsis

To further evaluate the effect of standard-of-care therapies on inflammation in patients with type 1 GD we will expand our analysis of inflammatory markers, by including novel markers such as C5a and hepcidin and examine its relationship with other GD biomarkers. We will analyze samples from patients who are stable on therapy and who are untreated in comparison to healthy controls.
 
PI: Reena Kartha, PhD
Co-Investigators: Marcia Terluk, PhD; Neal Weinreb, MD (University of Miami, FL)
Funding: Sanofi-Genzyme

Extracellular Vesicles as Potential Biomarkers and Therapeutic Target in Gaucher Disease

Project Synopsis

Neuroinflammation in GD is increasingly being considered as a major factor contributing to the complex neurological symptoms associated with this disease.  Extracellular vesicles (EVs) are small sub-cellular particles extruded by many cell types including platelets, macrophages and neurons. Via their cargo, that include proteins, RNAs, microRNAs and presumably lipids, they are a major vehicle for cell-cell communication and regulate cellular networks that are separate and remote from their cell of origin. Notably, EVs  are known to cross the blood-brain barrier and excess lipids can be taken up by brain microglia triggering neuroinflammation. The primary objective of this project is to understand the alterations in the biogenesis of EVs and its cargo and how this affects its role in intercellular communication as a consequence of defects in lysosomal function in GD.
 
PI: Reena Kartha, PhD
Co-Investigators: Jae Roh, PharmD; Marcia Terluk, PhD; Neal Weinreb, MD (University of Miami, FL)
Funding: Takeda Pharmaceutical Company

Magnetic Resonance Spectroscopy Biomarkers in Type 3 Gaucher Disease (GD3)
Project Synopsis

Project Synopsis

Type 3 GD (GD3) is a neuronopathic form of GD.  However, there is a lack of promising biomarkers that can track disease progression. The primary goal is to evaluate alterations in neurometabolites in patients with GD3 using Magnetic Resonance Spectroscopy (MRS). This will allow us to identify novel MRS biomarkers in these patients that can be useful as treatment response biomarkers.
 
PI: Reena Kartha, PhD
Co-Investigators: Neal Weinreb, MD (University of Miami, FL); Marcia Terluk, PhD
Funding: Sanofi-Genzyme

Other Projects

Oral N-acetylcysteine for treatment of hypoglycemia associated autonomic failure

Project Synopsis

The purpose of this project is to evaluate N-acetyl cysteine (NAC) as a therapy for the prevention and treatment of hypoglycemia associated autonomic failure (HAAF) in patients with type 1 diabetes. Impaired awareness of hypoglycemia occurs in approximately 25% of adults with type 1 diabetes and is associated with a six fold higher risk of having severe hypoglycemia that requires the assistance of another to recognize and treat. HAAF is also the primary barrier to achieving the level of glucose control necessary to prevent the microvascular complications of the disease and contributes to the mortality seen in patients with T1DM. This is a single center, double blind randomized cross-over design trial that will compare the impact of N-acetylcysteine (150 mg) vs. saline infusion during experimental hypoglycemia on day one on the responses to experimental hypoglycemia on day two. Primary endpoint will be the within person difference in epinephrine secretion during the morning episodes of hypoglycemia on days one and two under the two treatment conditions. As a secondary endpoint the exposure-response relationships will be explored.

PI: Elizabeth Seaquist, M.D.
Co-Investigators:  Amir Moheet, M.D.; Lisa Coles, Ph.D.; Lynn Elberly
Funding: JDRF

Translational Pharmacology Research Fellowship

Project Synopsis

The Translational Pharmacology Research fellowship is a postdoctoral position offered to doctoral degree holders (PharmD, MD, and/or Ph.D.) interested in the area of rare disease research, specifically Gaucher disease (GD). This fellow participates in hypothesis development and design of translational/clinical research, study execution, data generation, analysis, interpretation, and dissemination of key findings. The goal of this fellowship is to provide comprehensive research training in Gaucher disease that will facilitate the fellow to pursue a career in translational pharmacology. This is fundamental in moving this field of study forward as GD continues to intrigue everyone who is touched by this condition. The objectives are: 1) Develop an in-depth understanding of lysosomal diseases, specifically Gaucher disease; 2) Understand intricacies and challenges of rare disease clinical research; 3) Integrate and apply this knowledge and skills in the design and execution of a pilot biomarker research study in Gaucher disease; and, 4) Develop a professional identity as a lysosomal researcher by participating and presenting at international working groups, conferences and publishing the research.
 
PI: Reena Kartha, PhD
Funding: Sanofi-Genzyme

Oral N-acetylcysteine for treatment of hypoglycemia associated autonomic failure

Project Synopsis

The purpose of this project is to evaluate N-acetyl cysteine (NAC) as a therapy for the prevention and treatment of hypoglycemia associated autonomic failure (HAAF) in patients with type 1 diabetes. Impaired awareness of hypoglycemia occurs in approximately 25% of adults with type 1 diabetes and is associated with a six fold higher risk of having severe hypoglycemia that requires the assistance of another to recognize and treat. HAAF is also the primary barrier to achieving the level of glucose control necessary to prevent the microvascular complications of the disease and contributes to the mortality seen in patients with T1DM. This is a single center, double blind randomized cross-over design trial that will compare the impact of N-acetylcysteine (150 mg) vs. saline infusion during experimental hypoglycemia on day one on the responses to experimental hypoglycemia on day two. Primary endpoint will be the within person difference in epinephrine secretion during the morning episodes of hypoglycemia on days one and two under the two treatment conditions. As a secondary endpoint the exposure-response relationships will be explored.

PI: Elizabeth Seaquist, M.D.
Co-Investigators:  Amir Moheet, M.D.; Lisa Coles, Ph.D.; Lynn Elberly
Funding: JDRF

GCC 1906: Rare Diseases: What it Takes to Be a Medical Orphan

Project Synopsis

This course will comprise of weekly seminars and related readings on topics related to the understanding of rare diseases and the economics, regulatory and public policy aspects of development of drugs (orphan products) to treat these conditions in the US and across the globe. In this highly interactive course, students will learn from and network with researchers, healthcare professionals and business leaders and gain sufficient background to appreciate the scope of this multidisciplinary field. Students will work in teams with a patient advocacy organization to learn firsthand the challenges related to the diagnosis and treatment of a specific rare disease, barriers to research and development and deliver possible solutions to a specific challenge that they have identified.
 
PI: Reena Kartha, PhD
Funding: Office of Undergraduate Education

Recently Completed

ESETT: Established Status Epilepticus Treatment Trial (Pharmacology Core)

Project Synopsis

ESETT is multicenter, randomized, blinded, comparative effectiveness study of fosphenytoin (FOS), valproic acid (VPA) or levetiracetam (LVT) in the emergency department treatment of patients with benzodiazepine (BDZ) refractory status epilepticus (SE). The main objective is to determine the most effective and/or least effective treatment of BDZ refractory SE among patients older than 2 years. The primary outcome is clinical cessation of status epilepticus, without recurrent seizures, life-threatening hypotension or cardiac arrhythmia, or use of additional anti-seizure medications within 60 minutes of the start of study drug infusion. The drug dosing regime in ESETT is weight-based, patients weighing < 75Kg receive FOS 20 mg/Kg, or VPA 40 mg/Kg, or LVT 60 mg/Kg, but those weighing more than 75 Kg receive fixed doses of 1500 mg FOS, 3000 mg VPA and 4500 mg LVT. As an ancillary study, we are proposing the evaluation of drug exposure and response relationships.

PIs: Jaideep Kapur, MD; Robert Silbergleit, MD; James Chamberlain, MD; Jordan Elm, PhD; James Cloyd, PharmD
Co-investigators (ESETT): Lisa Coles, PhD
Co-investigators (PK-PD only): Richard Brundage, PhD; Vijay Ivaturi, PhD; Abhishek Sathe, MS.
Funding: NIH NINDS

MicroRNAs as Novel Biomarkers in Prolonged Seizures: Potential for Early Identification of Epilepsy

Project Synopsis

In this study, we will use a “two-hit” mouse model of epileptogenesis to understand the effect of seizures on miRNA expression in different brain regions. Seizures in immature animals cause subtle functional changes without causing cell death; however, this first hit (early seizure) can drastically alter the response to repeated seizures (second hit) later in life. This mimics the clinical characteristics of children with prolonged seizures. Thus a “two-hit” approach is a clinically relevant model of epilepsy and examining microRNA expression in brain and blood can provide information on the utility of microRNAs as diagnostic and prognostic biomarker of epilepsy.

PI: Reena Kartha, PhD
Co-Investigators: James Cloyd, PharmD; Sookyong Koh, MD (Emory University)
Funding: College of Pharmacy Grants Award Program (GAP)

Circulating MicroRNAs as Potential Biomarkers for Epilepsy

Project Synopsis

The long term goal is to evaluate the potential use of circulating microRNAs as clinical biomarkers in epilepsies. In this project, we will examine the temporal variation in blood microRNA expression following seizures in canines with naturally occurring epilepsy. Towards this end we will collect blood samples from these dogs prior to and immediately after a seizure episode at different time points. Circulating microRNAs will be analyzed using small RNA sequencing approach to understand changes in expression following a seizure.

PIs: Reena Kartha, PhD;  Edward E Patterson, DVM, PhD
Co-investigators: Bridget Curtin;  James Cloyd, PharmD; Anne Sarver, PhD; Subbaya Subramanian, PhD
Funding: American Kennel Foundation


MicroRNAs as Clinical Biomarkers to Understand Phenotypic Heterogeneity in Tuberous Sclerosis Complex

Project Synopsis

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder due to mutations in either TSC1 or TSC2 gene resulting in variable phenotypic expression. Epilepsy is the most common presenting symptom in TSC with approximately one-third of patients developing intractable epilepsy.The objective of this project is to determine circulating microRNA expression signatures in patients with TSC. We hypothesize that in comparison to healthy individuals, blood samples from patients with TSC have a unique miRNA expression signature. The dysregulated miRNAs can potentially cause differential gene expression contributing to the varied phenotypic spectrum in adults with TSC, including intractable epilepsy.

PI: Reena Kartha, PhD
Co-investigators: Mike Frost, MD; James White, MD; Nithin Agarwal, MD (Minnesota Epilepsy Group)
Funding: TBD

Lorenzo's oil in the Treatment of Adrenoleukodystrophy

Project Synopsis

X-linked adrenoleukodystrophy (ALD) is a genetic disorder leading to accumulation of saturated very long chain fatty acids (VLCFAs; mainly C26:0) in tissues. This accumulation causes demyelination of neurons in the brain and adrenal dysfunction. Childhood cerebral ALD (CCALD) is the most severe and devastating form of this disease and affects school-age boys, leading to death in 2-3 years. Lorenzo’s oil (LO) is believed to competitively inhibit the elongation of long chain fatty acids to VLCFAs and clinical studies have shown a reduction in plasma VLCFAs in  patients receiving LO. Additionally, literature suggests LO may reduce the development of cerebral involvement in ALD children, but studies on outcomes are conflicting. This is partially due to variability in dosing across studies and a complete lack of information on the pharmacokinetics and pharmacodynamics that characterize the dose-response relationship. The primary objective of this project is to determine the pharmacokinetics of erucic acid (a component of LO) in patients with X-linked ALD. This information will help optimize LO dosing in order to obtain desirable outcomes.

PIs: Mariam Ahmed, PhD; Gerald Raymond MD
Co-investigators: Reena Kartha, PhD; Richard Brundage, PharmD, PhD;  Bradley Carlin, PhD; James Cloyd, PharmD;
Funding: CTSI Translational Research Development Program

Improved Therapy for Late-stage Adrenoleukodystrophy

Project Synopsis

Childhood cerebral adrenoleukodystrophy (c-ALD) is an X-linked peroxisomal disorder affecting approximately 20,000 boys that results in demyelination of the CNS and early death in affected boys. Hematopoietic stem cell transplantation (HSCT) halts disease progression and extends life when c-ALD is diagnosed and treated at an early stage. There is, however, no known effective therapy for late-stage c-ALD although HSCT is offered at some centers. Survival and neurological outcomes are significantly worse in late-stage as compared to early-stage disease. N-acetylcysteine (NAC) is an antioxidant that reduces free radicals and facilitates glutathione biosynthesis. Our research team administered NAC to reduce oxidative damage and potentially render late-stage disease amenable to HSCT. The results indicate that IV NAC therapy, in conjunction with a reduced intensity transplant, significantly improves survival of boys with late stage-disease as compared to HSCT alone. Our studies are focusing on NAC clinical pharmacology and include both clinical and cell-based in vitro research . The goal of our research is to develop safer, more effective therapies for c-ALD including use of NAC as preventive therapy in children with early-stage disease.

PIs: James Cloyd, PharmD, Paul Orchard, MD
Co-investigators: Jakub Tolar, MD, PhD; Richard Brundage, PharmD, PhD; Reena Kartha, Gerald Raymond, MD; Troy Lund, MD, PhD; Lisa Coles, PhD; Jie Zhou, PhD; Mary Holmay, PhD
Past Funding: UMN Academic Health Center Faculty Development Grant

Effects of Yoga on Oxidative Stress, Motor Function and Psychosocial Well-being in Individuals with Parkinson’s Disease

Project Synopsis

Parkinson’s disease (PD) is a progressive neurodegenerative condition, in which motor and nonmotor features are currently not being sufficiently managed. Although the pathology of PD is complex, oxidative stress is recognized as a potential factor in the pathogenesis of PD. Hatha yoga has been shown to reduce oxidative stress in people with chronic health problems such as hypertension and diabetes; and improve gait, physical function, and quality of life in people with neurological disorders such as stroke and multiple sclerosis, however, studies carried out on the effects of yoga in PD are sparse. It is crucial to assess whether yoga is able to improve symptoms and alter the underlying biology of PD. The purpose of this study is to assess the effect of yoga on measures of oxidative stress, motor function, and psychosocial well-being as well as the feasibility and acceptability of implementing a yoga program in PD subjects.

PI: Corjena K. Cheung, PhD, RN
Co-Investigators: Jean Wyman, PhD; Jürgen Konczak, PhD; Paul Tuite,MD;  Reena Kartha, PhD; Catherine Justice, DPT
Funding: Grant-in-Aid of Research, Artistry and Scholarship Program, Midwest Nursing Research Society (MNRS)

Oral UDCA in Parkinson’s disease

Project Synopsis

We are interested in understanding the bioenergetic impairments that underlie Parkinson’s disease (PD) and evaluating treatments that may improve abnormal mitochondrial function that is present in PD. High field - 7 tesla (T) - magnetic resonance spectroscopy (MRS) is able to non-invasively assess for changes in brain energetics and will be used to evaluate the effects that repeated oral doses of the mitochondrial enhancer ursodeoxycholic acid (UDCA) has on brain bioenergetics derived from MRS measurements. The primary aim of the study is to measure plasma UDCA levels in individuals with PD at baseline and after four weeks of repeated high doses of oral UDCA (50mg/kg/day) and combine results obtained using MRS brain scans along with peripheral measurements of bile acids (e.g., total UDCA). Secondary aim of the study is to characterize oral UDCA pharmacokinetics and develop a pharmacokinetic/pharmacodynamic model to characterize the relationship between peripheral measurements of UDCA (and associated conjugates) and peripheral measures and/or central (brain) bioenergetic measurements.

PIs: Wei Chen, Ph.D.; James Cloyd, Pharm.D.
Co-Investigators:  Lisa Coles, Ph.D; Paul Tuite, M.D.; Xiao-Hong Zhu
Funding: University of Minnesota, Academic Health Center