RARE DISEASES CLINICAL RESEARCH NETWORK
Spastic Paraplegia Centers of Excellence Research Network |  |
Advancing understanding and treatment of hereditary spastic paraplegia (HSP), a large group of inherited disorders that affect the long nerve pathways carrying movement signals from the brain down the spinal cord to the legs. | |
Principal Investigators
Boston Children's Hospital
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TOP PUBLICATION
JOURNAL: Brain
DOI: 10.1093/brain/awg150
Hereditary spastic paraplegia type 4 (SPG4) is the most common form of hereditary spastic paraplegia. SPG4 is caused by changes in the SPAST gene. People with SPG4 commonly experience difficulty walking due to muscle weakness and spasticity (muscle rigidity) in the legs, as well as hyperreflexia (overactive bodily reflexes), urinary urgency or bladder dysfunction, and mild loss of vibration sense in the feet. Symptoms and time of disease onset can be very different from person to person, even within the same family. Not much is known about the natural history of SPG4, making it difficult to conduct clinical trials and find new therapies.
In this study, researchers investigated genotype–phenotype correlations and the natural history of early-onset SPG4. The team used deep phenotyping to analyze 206 patients with genetically confirmed SPG4 from seven international centers. Researchers also studied data from an additional 146 patients from previous studies.
Results provide the most detailed natural history of SPG4 to date, creating a framework that links specific genetic variants to different clinical trajectories. Authors note that these findings can improve care and optimize clinical trial design for SPG4.
What was your consortium's most significant achievement from the past year?
Darius Ebrahimi-Fakhari, MD, PhD, Principal Investigator, SP-CERN: In its first year, SP-CERN enrolled more than 160 participants across the network—a pace that establishes the largest prospective cohort assembled to date for hereditary spastic paraplegia and positions the consortium to answer natural history and biomarker questions that no single center could address. This recruitment was made possible by the rapid operationalization of the network: harmonized standard operating procedures were established and adopted across all participating sites, three new affiliate sites were added to extend geographic reach and referral capacity, and the consortium completed validation work on a new clinician-reported outcome measure, the modified Spastic Paraplegia Rating Scale (mSPRS), which is now available for use in future interventional trials. Consortium investigators also published more than 10 peer-reviewed papers over the same period, reflecting both the productivity of the network and the collaborative culture it has built.
EARLY CAREER INVESTIGATOR SPOTLIGHT
What are your research goals?
Dr. Agianda: My research goal is to accelerate the path to effective therapies for children with rare neurogenetic diseases by identifying and validating blood-based biomarkers that can serve as objective, minimally invasive outcome measures in clinical trials. I focus on hereditary spastic paraplegia (HSP), a heterogeneous group of disorders affecting the corticospinal tract, where the absence of validated biomarkers has slowed trial design and made it difficult to detect meaningful treatment effects over short timeframes. Using plasma proteomics platforms, my broader aim is to identify a biomarker robust enough to support regulatory-grade trial endpoints, so that as targeted and gene therapies reach clinical testing, sponsors and families have reliable ways to measure whether a therapy is working, shortening the distance between discovery and meaningful change in children's lives.
Patient Advocacy Impact Story
