A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)
Raj Rajagovindan1, Benjamin Matys1, Elizabeth Finger2, Jeffrey Gelfand3, Stuart Isaacson4, Wolfgang Köhler5, Rajeev Kumar6, David Lynch7, Jennifer Orthmann-Murphy8, Ludger Schöls9, Nicole Wolf10, Andreas Meier1, Spyridon Papapetropoulos1, Zbigniew Wszolek11
1Vigil Neuroscience, 2Western University, 3University of California, 4Parkinson’s Disease and Movement Disorders Center of Boca Raton, 5University of Leipzig Medical Center, 6Rocky Mountain Movement Disorders Center, 7University College London, 8University of Pennsylvania, 9University of Tuebingen, 10Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University, and Amsterdam Neuroscience, 11Mayo Clinic- Jacksonville
Objective:
Characterize the natural history of ALSP by imaging, biomarkers, and standardized clinical measurements to inform the design of future clinical trials testing novel therapeutics for ALSP.
Background:
ALSP is a rare, rapidly progressing fatal neurologic disorder commonly caused by dominant variants in the CSF1R gene. The pathological hallmarks include demyelination of brain white matter, swollen axons, and pigmented glial cells. Clinically, ALSP is characterized by a constellation of symptoms including personality changes, cognitive dysfunction and motor impairments. There are no FDA approved treatments for ALSP. Limited natural history data is available to inform development of therapeutics for ALSP.
Design/Methods:
This is a prospective, multicenter, natural history study of patients with ALSP and asymptomatic carriers of CSF1R gene mutations. Up to 36 participants will be enrolled and followed for 24 months. Clinical assessments (cognitive, motor, functional, psychiatric, severity of illness, and caregiver burden) and MRI will be collected at Screening and at months 6, 12, 18, and 24. MRI severity score (Sundal et al 2012), white matter lesion and regional brain volumes will be derived. Blood and CSF (in a subset of participants) biomarkers of disease will be measured at specific visits.
Results:
28 participants with confirmed CSF1R gene mutation meeting study eligibility criteria have been enrolled as of 9/2/2022. Among these, 17 were symptomatic and 11 were asymptomatic carriers, 13 were women and mean age at Screening visit was 46±13 years. Study enrollment is ongoing. Detailed study design and baseline characteristics of enrolled participants will be presented.
Conclusions:
This is the first systematic prospective study characterizing the natural history of ALSP due to CSF1R gene mutations leveraging standardized clinical, imaging and biomarker measurements. The outcome of this study is expected to inform on optimal biomarker and clinical endpoints and design of therapeutic intervention studies in ALSP.