N-of-1 Trial Design
Our team aims to develop a fully integrated N-of-1 clinical trial platform with personalized evaluation of repurposed therapies for selected rare diseases. Available online, our n-of-1 platform will include a number of modules that facilitate implementing n-of-1 clinical trials in daily practice, hence making clinicians comfortable to use the approach in their practice. An N-of-1 clinical trial platform with personalized evaluation of drug effects permits direct estimation of individual treatment effects, facilitates finely graded individualized care by generating data, enhances therapeutic precision, improves patient outcomes, and reduces costs, while at the same time improves patients’ satisfaction and safety. Single patient trials will also assess safety in a rigorous and systematic way – therefore protecting patients through the early detection of unexpected events and at the same time generating reliable data to inform clinicians through scientific publications. Finally, data from the single patient trials that collected using standardized treatment protocols and outcomes assessments, could be also incorporated into the larger datasets in order to generate evidence-based knowledge on the larger population scale.
Repurposable drug in vitro SLC6A8 screening
Cerebral creatine transporter deficiency is a genetic cause of intellectual disability. Affecting the uptake of creatine to the brain, patients have almost undetectable levels of this important substance in their nervous system. Current treatment with creatine supplements has limited therapeutic effects. Therefore, the development of new treatments is urgently needed. The goal of this study is to use our methods (including 3D computer modelling and in-silico drug screening/computer-aided drug design) to screen different creatine supplements and drugs for potential rescue of creatine transporter function associated with SLC6A8 variants for patients with the ultimate goal to develop a personalized therapy for our current patient. The development of methods for screening SLC6A8 function in response to existing and new therapeutic molecules will help to customize therapies according to individuals’ genotype and improve outcomes (precision medicine). The principal investigator for this project is Dr. Sylvia Stockler and the co-investigator is Dr. Peter Axerio-Cilies.
Repurposable drug in vitro SLC6A1 screening
Genetic variants in SLC6A1 cause a spectrum of neurodevelopmental disorders characterized by epilepsy, global developmental delay and intellectual disability, autism and psychiatric disorders such as schizophrenia. Myoclonic‐atonic epilepsy is the most frequently observed seizure type. Standard treatment for controlling the epilepsy is valproic acid by itself or in combination with other anti-epileptic drugs or the ketogenic diet. This treatment helps with seizure activity but does not help the underlying issue and therefore this treatment does not help with intellectual disability, language impairment and behavioural issues. Therefore, there is an urgent need to identify new treatments that would treat the underlying neurological issues caused by variants on SLC6A1. Our goal is to develop a drug repurposing pipeline to treat the underlying neurological issues caused by variants on SLC6A1.
Pompe disease is a rare and fatal muscle disease resulting from an underlying deficiency of the lysosomal hydrolase, acid alpha glucosidase. Other names for Pompe disease include Glycogen storage disease type II (GSD-II), acid maltase deficiency (AMD) and glycogenosis type II. Pompe disease may be easier to identify in infants simply because the signs and symptoms are more pronounced, and the urgency of the situation is often apparent. Currently, there is no approved, curative treatment for Pompe disease. Palliative and supportive care provides the mainstay of management. Pompe Registry is an observational study, collecting data from the patients' medical charts and electronic health records. This is an industry sponsored study, for which the principal investigator is Dr. Sylvia Stockler. The purpose of the registry is to track the natural history of Pompe disease and to collect information on clinical, biochemical, patient-reported and other potential clinical and biochemical outcomes in patients, diagnosed with this ultra-rare condition. The registry will be collecting "real world" data (as per clinical practice), no intervention will be done.
Families’ Health Care Experiences
The purpose of this study is to understand the health care experiences of families of children with IMDs, from the perspective of the parent or guardian. The University of Ottawa team has developed a series of online questionnaires using a secure website, and possibly, will conduct interviews with the caregivers via telephone. Dr. Sylvia Stockler is a collaborator for this project; the principal investigator of the project is Dr. Beth Potter (University of Ottawa). Dr. Prabir Chakraborti is the co-investigator of the study (UO). The research activities are taking place at the University of Ottawa (Children's Hospital of Eastern Ontario). Our role in this study is to identify potential participants at BC Children's Hospital, approach them, and provide them with the initial study information. The patients will be informed about the study by the doctor or dietitian. If caregiver agrees to proceed - they will be given the postcard with the link to the brief online "eligibility survey" or, if they agree to, they can complete the survey on the phone. If they complete the survey, their contact information will be available for the Ottawa team and further communications and informed consent process and the study procedures will be organized by Ottawa team.
The Gaucher Registry is an ongoing, post-marketing, observational registry that tracks outcomes of routine clinical practice for patients with Gaucher disease. The data collected will provide information to better characterize the natural history and progression of Gaucher disease as well as the clinical response of patients whose physicians have prescribed ERT. The principal investigator for this industry sponsored-study is Dr. Sylvia Stockler and the co-investigator is Dr. Ramona Salvarinova (a metabolic physician at Biochemical Genetics at BC Children’s). The Gaucher Registry collects participants' data in order to monitor disease progress for patients diagnosed with Gaucher disease and who are on treatment (i.e., Enzyme Replacement Therapy- ERT). Subjects who are not on ERT can also enroll in which care the Registry monitors the natural progress on the disease.
MPS I registry
The purpose of the mucopolysaccharidosis I (MPS I) Registry is to track the natural history and outcomes of patients with MPS I. The principal investigator for this industry-sponsored study is Dr. Sylvia Stockler. Mucopolysaccharide storage (MPS) disorders are caused by deficiencies of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). The accumulation of GAG substrates occurs in a variety of tissues. The primary objectives of the Registry are: to evaluate the long-term effectiveness and safety of a specific drug, to characterize and describe the MPS I population as a whole, including the variability, progression, and natural history of MPS I, and to help the MPS I medical community with the development of recommendations for monitoring patients and reports on patient outcomes to optimize patient care. The MPS I Registry is a voluntary, ongoing, observational program for patients with MPS I; no experimental intervention is involved. Data collected through the Registry will be entered into a database and analyzed. This long-term program will proceed for a minimum of 15 years.
GSD Type Ia Gene Therapy
The principal investigor for this industry-sponsored this study is Dr. Sylvia Stockler and the co-investigator Dr. Ramona Salvarinova. It is a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients with Glycogen Storage Disease Type Ia. GSD type Ia is lysosomal monogenic disease caused by the mutation in G6PC gene. The mutation affects the way the body utilizes glycogen – the main source of energy, stored in the liver. Individuals with glycogenosis experience deficit in enzyme that breaks glycogen; thus, glycogen accumulates in the liver. Current standard of treatment is regular and continuous cornstarch intake (even at night) to prevent sudden decrease in blood glucose levels. A gene therapy being developed for the treatment of glycogen storage disease type Ia (GSDIa). This is a pivotal study to determine the efficacy and safety of gene therapy in adolescents and adult patients with GSDIa. The experimental treatment of this study is one time injection of gene vector. This study design is randomized double-blind, placebo-controlled. The primary objective is to evaluate the efficacy of the gene therapy to reduce or eliminate dependence on glucose replacement therapy to maintain euglycemia and to maintain or improve the quality of glucose control.
An Open-Label Study of an Experimental Drug in Subjects with Metachromatic Leukodystrophy
The principal investigator for this industry sponsored study is Dr. Sylvia Stockler and the co-investigators are Dr. Ramona Salvarinova (a metabolic physician at Biochemical Genetics at BC Children’s) and Dr. Ashutosh Singhal (a pediatric neurosurgeon at BC Children’s). Metachromatic leukodystrophy (MLD) is a genetic disease that leads to the accumulation of sulfated glycosphingolipids in the nervous system (spinal cord and the brain). Clinically, MLD presents with regression of the developmental milestones, rapid neurological and cognitive decline and death. Currently, there is no treatment available for patients with this condition. The objective of this clinical trial is to investigate the safety and efficacy of the experimental drug (enzyme replacement therapy) for MLD. Study participants are children diagnosed with late infantile MLD on various stages of the disease progression. The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of the gene therapy on gross motor function and to stabilize or slow progression of motor dysfunction in pediatric subjects with late infantile MLD.
Fabry Disease Registry
The principal investigator for this industry-sponsored study is Dr. Sylvia Stockler. Fabry disease is rare and results from the absence of or a markedly deficient lysosomal enzyme called α-galactosidase A (α-Gal A). The Fabry Registry is a multi-center, international, longitudinal, observational program for patients with Fabry disease that was designed to track the natural history and outcomes of patients. The ultimate goal of this study is to help better guide and assess therapeutic intervention, to assist the Fabry medical community with the development of recommendations for monitoring patients, and to provide reports on patient outcomes to optimize patient care.
The principal investigator for this industry-sponsored study is Dr. Sylvia Stockler. The MARS registry aims to collect patient data and provide information to better characterize the natural history and progress of MPS IV A in both treated and untreated patients of all ages. This project will also help evaluate the long-term efficacy and safety of the drugs that are being tested. The registry might also help doctors and researchers learn more about MPS IV A and its treatment and progression. This will be done over a period of 10 years.