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Current Projects

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.

Seizure Disorders

Seizure Disorders

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

Project Synopsis
The long term goal is to evaluate the potential use of microRNAs as clinical biomarkers in pediatric epilepsies. In this study, we will use a “two-hit” mouse model of epileptogenesis; the gradual process by which a normal brain develops epilepsy. 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 complex febrile 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.

PIs: Reena Kartha, PhD; James Cloyd, PharmD
Sponsor: College of Pharmacy Grants Award Program (GAP)

Identifying New Therapies for Infantile Spasms

Project Synopsis
Infantile spasms (IS) are epileptic seizures in infants which often lead to emergence of other types of seizures, cognitive deficits, and neurodevelopmental disabilities. This project will evaluate the efficacy and tolerability of drug therapies in mouse models of infantile spasms in order to identify treatments that achieve rapid and sustained suppression of spasms and determine whether these are effective and safe in infantile spasms of various pathologies. The goal of this project is to identify new treatments for infantile spasms that have rapid onset and stop spasms early with anti-epileptic and disease modifying effects that persist through adulthood.

PIs: Aristea Galanopoulou MD, PhD; Rodney Scott, MD; Gregory Holmes, MD; James Cloyd, PharmD
Co-Investigators: Lisa Coles, PhD, Krista Johnson, PhD
Funding: Citizens United for Research in Epilepsy, Department of Defense

Use of Topiramate for Neuroprotection and Seizure Control in Neonates

Project Synopsis
The long-term goal of this project is the development of a neuroprotectant and a safer, more effective treatment of neonatal seizures caused by hypoxic-ischemic brain injury in newborns. Such injuries, although rare affecting fewer than 12,000 babies per year, are a significant medical problem with a high mortality rate, grave neurological sequelae including impaired cognition and neonatal seizures, and serious treatment-related adverse effects that can cause further brain injury. Intravenous topiramate holds the promise of controlling seizures and providing neuroprotection in newborn babies. Research establishing the safety and dosing will begin in adults and eventually move to children, then newborns. Phase I studies involving 20 adult patients taking oral topiramate and 12 healthy volunteers have been completed. The final phase of this project will be the completion of a randomized, controlled clinical trial. A safer, more effective treatment for neonatal seizures combined with the potential for neuroprotection would represent a significant advance in the care of babies with brain injury.

PI: James Cloyd, PharmD
Co-Investigators: Robert Kriel, MD; Richard Brundage, PharmD, PhD
Current Funding: CyDex
Past Funding: FDA Orphan Products Grants Program, Epilepsy Research Foundation
Commercial Partner: CyDex

Investigation of Antiepileptic Drug Pharmacology in Canine Epilepsy

Project Synopsis
This project involves the use of dogs with epilepsy to characterize the pharmacokinetic and pharmacodynamic properties of approved and investigational antiepileptic drugs (AEDs). The canine epilepsy model permits studies on the differential effects of AEDs 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.

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

Development of Responsive Pharmacotherapy in Canine Partial Epilepsy

Project Synopsis
This project is dedicated to the development of responsive pharmacotherapy for individuals with epilepsy. A Seizure Advisory System (NeuroVista, Inc), which is capable of predicting and signaling seizure occurrence before the event, will be coupled with administration of an antiepileptic drug at the time of high seizure likelihood. This new approach to epilepsy pharmacotherapy offers the potential of significantly reducing amount of drug patient require for seizure control.

Investigators: Greg Worrell, MD, PhD; James Cloyd, PharmD; Ned Patterson, DVM, PhD; Brian Litt, PhD, MD; Lisa Coles, PhD; Doug Sheffield, DVM, PhD
Past Funding: NeuroVista, NIH NINDS 

Intranasal Benzodiazepines for Seizure Emergencies

Project Synopsis
The long-term goal of this project is the development of a novel, FDA-approved, intranasal benzodiazepine delivery system for the treatment of seizure emergencies in children and adults. Some patients with epilepsy, particularly those who are developmentally disabled, are prone to seizure clusters and status epilepticus. Seizure emergencies have devastating effects on the patient’s health and quality of life. Delays in treatment may result in refractory seizures, increased morbidity and mortality, and higher medical costs. The availability of a safe, effective, and easily administered therapy allowing patients, parents, or caregivers to initiate treatment at the onset of a seizure emergency would greatly improve the management of epilepsy.

PIs: James Cloyd, PharmD; Robert Kriel, MD
Past Funding: Neurelis, Inc

Development of Water-soluble Benzodiazepine Prodrugs to Treat Seizures Emergencies

Project Synopsis
The goal of this project is to develop a highly water-soluble benzodiazepine prodrug intended for nasal administration that undergoes rapid metabolism in nasal epithelium or blood to an active drug. Such a compound would permit formulation of a highly concentrated drug solution capable of delivering clinically-relevant doses in small volumes i.e. < 200 microliters and which would cause minimal local tissue irritation and injury. Target mechanisms for biotransformation are those mediated by enzymes known to be present in nasal tissue. Compounds will be evaluated for rate of biotransformation and permeation using in vitro cell cultures. Those showing the most promise will then be studied in dogs with epilepsy that have implanted intracranial EEGs.

PI: Gunda Georg, PhD
Co-Investigators: Jim Cloyd, PharmD; Ron Siegel, DSc; Ilo Leppik, MD; Ned Patterson, DVM, PhD
Funding: UMN Academic Health Center Faculty Development Grant

Oxidative Stress in Neurodegenerative Disorders

Oxidative Stress in Neurodegenerative Disorders

Oxidative Stress-related Biomarkers in Gaucher Disease: a Preliminary Study

Project Synopsis
The primary objective of this study is to evaluate oxidative stress in patients with Gaucher disease using a series of biomarkers and correlate with clinical diagnostic biomarkers.  Additionally, the relationships between oxidative stress and variables including therapy or intervention (for example ERT, SRT) and disease severity will be evaluated. We hypothesize that compared to healthy individuals subjects with GDI will have increased oxidative stress which can be normalized by intervention. Further we hypothesize that there is a relationship between these biomarkers of oxidative stress and disease progression or response to therapy.
: Reena Kartha, PhD; James Cloyd, PharmD
Sponsor: Genzyme

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. Additionally, NAC and glutathione pharmacokinetics will be characterized in this population with the intent to construct models linking pharmacokinetics with biomarker changes.

PIs: James Cloyd, PharmD; Reena Kartha, PhD
Sponsor: Lysosomal Disease Network, Pfizer

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
Collaborators: Jean Wyman, PhD; Jürgen Konczak, PhD; Paul Tuite,MD;  Reena Kartha, PhD; Catherine Justice, DPT
Sponsor: Grant-in-Aid of Research, Artistry and Scholarship Program, Midwest Nursing Research Society (MNRS)

A Model-based Approach to Optimize Lorenzo’s Oil Therapy in X-Linked 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 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, MS; Reena Kartha, PhD; Richard Brundage, PharmD, PhD; James Cloyd, PharmD; Gerald Raymond MD
Sponsors: 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 (Tolar et al, 2007). 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

Intravenous N-acetylcysteine for the Treatment of Gaucher’s and Parkinson’s Diseases

Project Synopsis
There is an emerging hypothesis that depletion of glutathione may play a role in both Gaucher and Parkinson’s diseases. These pilot projects will investigate the effect of a single 150 mg/kg intravenous and 140 mg/kg oral doses of N-acetylcysteine (NAC) on glutathione concentrations in specific areas of the brain using magnetic resonance mass spectroscopy. Simultaneously, NAC and glutathione concentrations are measured in plasma and red blood cells. In this preliminary study, we showed that a single intravenous 150 mg/kg dose of N-acetylcysteine increased blood glutathione redox ratios in those with Parkinson’s and Gaucher disease and healthy controls, which was followed by an increase in brain glutathione concentrations in all subjects. These results will set the stage for large trials evaluating the benefit of NAC in the treatment of Parkinson’s and Gaucher’s diseases.

PIs: Paul Tuite, MD; James Cloyd, PharmD
Co-Investigators: Gulin Oz, PhD; Lisa Coles, PhD, Mary Holmay, PhD; Sarah Hilbert
Past Funding: NIH-Lysosomal Disease Network



Prevention of Baclofen Withdrawal: Development of Intravenous Baclofen

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, while a larger, but unknown number of patients taking oral baclofen would benefit form an IV baclofen formulation when they are unable to take medications by mouth.

Co-PIs: Robert Kriel, MD; Co-PI: Linda Krach, MD
Co-Investigators: James Cloyd, PharmD; Lisa Coles, PhD; Suresh Argawal, PhD
Funding: Paralyzed Veterans of America, Medtronic, Inc

Other Projects

Other Projects

Assessing and Improving Orphan Product Development

Project Synopsis
The project is investigating orphan product development since the enactment of the Orphan Drug Act. Desired outcomes of the project include a better understanding of types of orphan drugs that have been, and are being, developed to treat rare disorders; identification of factors related to timely FDA approval of orphan drugs; and generation of information that can promote formulation of appropriate public policy regarding development of and access to orphan products.

Investigators: Sheiren Farag, PharmD, (PhD student); James Cloyd, PharmD, Steve Schondelmeyer, PharmD, PhD
Funding: FDA Office of Orphan Products Development, Drug Information Association

Post-PharmD Fellowship Clinical Pharmacotherapy and Pharmacogenetics of Inherited Metabolic Diseases

Project Synopsis
Enzyme replacement therapy for rare inherited metabolic diseases such a Pompe, Hurler’s, and Gaucher are life-extending, but expensive. Individualized titration and careful management of these biologics can ensure optimal outcomes while minimizing costs. The investigators have designed a residency for pharmacists that will provide them with the training needed to provide exceptional clinical care of patients requiring enzyme replacement therapy as well as the opportunity to develop research skills related to the pharmacotherapy of rare disorders.

Co-PIs: Jeanine Utz, PharmD; James Cloyd, PharmD
Co-investigator: Chet Whitley, MD, PhD
Funding: Genzyme

Use of N-acetyl cysteine for the Prevention and Treatment of HAAF

Project Synopsis
The overall goal of this study is to determine if N-acetyl cysteine (NAC) will be effective in the prevention and treatment of hypoglycemia associated autonomic failure (HAAF) in adults with type 1 diabetes.
Hypoglycemia occurs frequently in the lives of patients with type 1 diabetes. Recurrent hypoglycemia episodes closely spaced in time creates the syndrome of HAAF in which the hormone response to hypoglycemia is confusion or unconsciousness. 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 diabetes complications and contributes to the mortality seen in patients with type 1 diabetes. Despite the clinical importance of HAAF, effective strategies to prevent and treat the syndrome in humans have not yet been developed. In animal models, administration of NAC during episodes of hypoglycemia prevents the development of HAAF. Whether NAC will be beneficial in humans is unknown. We now intend to examine NAC’s efficacy as a therapy for HAAF. These experiments will provide the crucial first steps necessary to advance this readily available therapy as a potential treatment for this devastating complication of diabetes.

PI: Elizabeth Seaquist, MD
Co-investigators: Lisa Coles, PhD; James Cloyd, PharmD; Amir Moheet, MD; Lynn Eberly, PhD
Funding: Juvenile Diabetes Research Foundation