Guoyu Zhou1, Theresa Driscoll1, Supratik Nandi1, Kolette Cho1, Michael Terranova1, Kelly O'Leary1, Stacy Metcalf1, Megan Casey1, Sven Forner1, Robin Schubert2, Ralf Reilmann2, Amy Kuo1, Kendra Benisaro1, Aili Golubjatnikov1, Katherine Wong1, Michael Geschwind1
1UCSF, 2George Huntington Institute
Objective:
Identify potential biomarkers for future treatment trials in the presymptomatic phase of genetic prion disease (gPrD).
Background:
By the time patients with gPrD become symptomatic, potential treatments are unlikely to have benefit. Approximately 15% of human PrDs are genetic, caused by PRNP mutation. As a simple genetic test can identify mutation carriers from gPrD families before symptom onset (presymptomatic), this group is an ideal target for therapeutic trials to delay or prevent onset. To prepare for upcoming trials, we need biomarkers of the earliest changes prior to symptom onset.
Design/Methods:
Our preliminary data suggested we can measure such biological changes in presymptomatic gPrDs. Without formal funding, we evaluated ~110 participants, following them in an ad hoc manner (less than annually) since 2002. After obtaining NIH R56/R01 funding in 9/2018, we are assessing carriers and non-carrier family members approximately annually using a standardized assessment battery over a 2-day visit.
Results:
Approximately 196 gPrD participants from 73 families involving 20 PRNP mutations had research visits from 3/2002-8/2023, including 50 presymptomatic gPrD participants seen through our NIH grant who are from 29 families representing 6 common high penetrance PRNP mutations. 70% (of the 50) are carriers, 30% are non-carrier controls. These 50 had 92 visits prior to and during the NIH grant, with 26/50 participants having serial research visits, some prior to the NIH funding period. Participants have the following assessments: 3T MRI, neuropsychological testing, CSF, blood (for DNA, plasma, serum, RNA), genetic counseling, detailed history and neurological exam, informant measures, quantitative motor testing (qMotor), OCTs, skin biopsies (began 2022), and some had home sleep assessments. Recruitment continues.
Conclusions:
Long-term observational studies in presymptomatic gPrD are feasible. Serial evaluations are continuing, and we expect we will identify potential biomarkers of change over the course of presymptomatic gPrD, providing key data for future trials.