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Design of a Phase 1/2 study of an AAV9‐based gene therapy for fronto‐temporal dementia patients with pathogenic GRN mutations (PROCLAIM trial): Human/Trial design
Ist Teil von
Alzheimer's & dementia, 2020-12, Vol.16 (S9)
Erscheinungsjahr
2020
Quelle
Wiley Blackwell Single Titles
Beschreibungen/Notizen
Abstract
Background
The
GRN
gene encodes progranulin (PGRN), a secreted glycoprotein broadly expressed in the CNS and periphery in a variety of cells. PGRN is implicated in several physiological functions including as an activator of lysosome function, an anti‐inflammatory factor, a neurotrophic factor, and a growth factor. Patients suffering from fronto‐temporal dementia with
GRN
mutations (FTD‐GRN) carry a single mutation in the
GRN
gene, resulting in haploinsufficiency and an approximately 50% reduction in PGRN levels.
GRN
mutation carriers have an approximately 90% risk of developing FTD by age 75. FTD‐GRN is a rapidly progressing dementia with no approved treatment options. In FTD‐GRN patients, the delivery of a functional copy of the
GRN
gene by a recombinant adeno‐associated virus serotype 9 (rAAV9) directly to the CNS may normalize PGRN levels, potentially restoring lysosomal function and slowing neurodegeneration, thus resulting in modification of disease progression.
Methods
PROCLAIM is a Phase 1/2 randomized, open‐label, ascending dose study to evaluate the safety and efficacy of PR006 in patients with FTD‐GRN. The study will evaluate three dose levels of PR006 in ascending dose cohorts. A total of 15 patients with symptomatic‐stage FTD ascertained by the CDR plus NACC FTLD sub of boxes score will receive PR006 at a low, mid or high dose, administered sub‐occipitally intra cisterna magna. The primary objective is to evaluate safety and tolerability of PR006, as well as to quantify the change in PGRN levels in blood and CSF. Secondary objectives are to assess pharmacodynamic effects of PR006 on neurofilament light chain protein, clinical decline assessed by the CDR plus NACC FTLD instrument, and immunogenicity. Exploratory objectives include the assessment of clinical symptom burden, MRI measures of cortical atrophy and white matter hyperintensities, and biomarkers of neuroinflammation and astroglial pathology.
Result
The PROCLAIM trial is planned to open patient enrollment in 2020.
Conclusion
PROCLAIM will assess dose, safety, tolerability, biomarker and efficacy effects of PR006 and inform its further clinical development.
Sprache
Englisch
Identifikatoren
ISSN: 1552-5260
eISSN: 1552-5279
DOI: 10.1002/alz.040916
Titel-ID: cdi_crossref_primary_10_1002_alz_040916
Format
–
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