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Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results
Medicine and HealthNature Medicine

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results

J. Sevigny, O. Uspenskaya, et al.

Exciting breakthroughs in gene therapy with PR006 show promise in treating frontotemporal dementia caused by GRN mutations. This transformational research, led by a talented team of authors including Jeffrey Sevigny, Olga Uspenskaya, and others from Prevail Therapeutics, revealed encouraging safety and efficacy results, with all patients showing increases in crucial neuroprotective proteins. Join us on this journey to unlock new horizons in dementia treatment!... show more
Abstract
GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625.
Publisher
Nature Medicine
Published On
May 14, 2024
Authors
Jeffrey Sevigny, Olga Uspenskaya, Laura Dean Heckman, Li Chin Wong, Daniel A. Hatch, Ambika Tewari, Rik Vandenberghe, David J. Irwin, Dario Saracino, Isabelle Le Ber, Rebekah Ahmed, Jonathan D. Rohrer, Adam L. Boxer, Sebastian Boland, Patricia Sheehan, Alissa Brandes, Suzanne R. Burstein, Benjamin M. Shykind, Sitharthan Kamalakaran, Carter W. Daniels, E. David Litwack, Erin Mahoney, Jenny Velaga, Ilan McNamara, Patricia Sondergaard, Syed A. Sajjad, Yvonne M. Kobayashi, Asa Abeliovich, Franz Hefti
Tags
GRN mutationsfrontotemporal dementiagene therapyPR006AAV9 vectorneuroprotectionCSF progranulin
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