Translational Research in Rare Diseases

Research on rare diseases is faced with unique challenges and opportunities. Our research program combines basic science and clinical research to create and implement novel medical technologies and treatments. Our work is translational and patient-centered. Most of our research projects are inspired by patients and families we meet in the clinic. We take on areas where we see an unmet need and bring ideas from our clinical work to our laboratory (‘bedside to bench’). Vice versa, our basic science research program is targeted at understanding fundamental molecular disease mechanisms and at developing platforms for testing novel therapeutics, with the goal of ultimately implementing first-in-human and pivotal clinical studies (‘bench to bedside’). We aim to accelerate the time between laboratory research, development, and clinical application.

We study rare neurogenetic disorders in part because their cause can be defined with precision. Knowing the mutated gene – and therefore the defective or deficient protein it encodes – opens a direct path to the specific cellular abnormalities that drive dysfunction and disease. Rarity should not diminish the value of studying these conditions; it should be weighed against the considerable advantage they offer in dissecting disease pathogenesis. By identifying the earliest cellular changes – those most proximate to, and arising directly from, the protein defect – we can design more effective therapeutics. A drug that targets these initiating events can prevent the manifold downstream and collateral consequences that accumulate in the cascade underlying disease. The exemplar of such an early, targeted approach is gene replacement therapy: by supplying diseased cells with a wild-type copy of the culprit gene, it corrects the primary defect and aims to avert pathogenic effects altogether.

Precision neurotherapeutics will have their greatest near-term impact in rare disorders. But more prevalent, multifactorial neurologic diseases stand to benefit as well, because they often share pathogenic mechanisms with rare conditions. Even where a specific treatment does not generalize to larger populations, the insights gained into shared biology will reveal novel targets to pursue.

Creating Clinical Trial Readiness

How do we create the infrastructure for first-in-human and pivotal studies in rare diseases?

Discovering key disease mechanism

What are the molecular mechanisms that lead to hereditary spastic paraplegia?

Creating a platform for novel therapeutics

How can we leverage novel disease models and genomic tools to create therapeutics?

Conducting clinical trials

How do we design future trials for rare and ultra-rare diseases?

Ongoing Translational and Clinical Research Projects

Natural History Study for Early-Onset Hereditary Spastic Paraplegia (HSP-NHx) NCT04712812
Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq) NCT05354622
Spastic Paraplegia – Center of Excellence Network (SP-CERN) (NCT06553976)
A Retrospective Survey-based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes (EDS Study)
Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Dyskinetic Cerebral Palsy (VDCP) NCT05206513
Multi-centre Deep Brain Stimulation Registry (DBSR) NCT06585618
DBSMatchMaker – International Clinical Network for Pediatric DBS Cases
Registry and Natural History Study for Progressive Myoclonic Epilepsy 1A (EPM1-NHx) NCT06593951
Registry and Natural History of Epilepsy-Dyskinesia Syndromes (PEDS-NHx) NCT06967727

Ongoing Basic and Translational Research Projects

Comprehensive Preclinical Development of Small Molecule Modulators of Protein Trafficking to Restore AP-4 Deficiency
Characterize Axonal Multiomic Signatures of AP-4-Deficient Neurons
Identify and Validate Potential Disease Biomarkers of Axonal Pathology through Targeted Proteomics
A Functional Genomics Approach to Identify Modulators of AP-4-Related Protein Trafficking
Understanding the role of AP-4 and its cargo in early brain development
Development of a high-throughput small molecule screen for ADCY5-related disorder

Supporting the Rare Disease Community

We believe that the work of our laboratory should not only be confined to advancing science, but that we should also strive to engage the broader community. Through a variety of outreach efforts, we believe that we can help make our scientific communities more inclusive and learn from the diverse perspectives these experiences provide.