Abstract Details

Title AAV-Mediated Progranulin Delivery to a Mouse Model of FTD/CNL Causes T Cell-Mediated Toxicity

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S9 - Aging and Dementia: Clinical Trials and Novel Therapies (4:14 PM-4:25 PM)

Poster/Presentation
Number 005

Objective Progranulin (GRN) deficiency leads to frontotemporal dementia (FTD) in the case of haploinsufficiency and neuronal ceroid lipofuscinosis type 11 (CLN11) in the case of complete deficiency. Achieving sustained global expression of GRN could therefore lead to slowing or reversal of these diseases.

Background

Previous groups have shown that intraparenchymal GRN gene (GRN) delivery leads to modest rescue in mouse models of FTD and CLN11. AAV vectors are widely and safely used for CNS transduction in null models of many diseases. Given the difficulty of translating intraparenchymal delivery into humans, an intracerebroventricular AAV-mediated approach targeting either neurons or ependyma should result in sustained, widespread, and safe expression of GRN in a manner translatable to humans.

Design/Methods We used AAV9 to deliver GRN to the lateral ventricle of Grn null mice to achieve global transduction. We also used AAV4 to specifically target ependymal cells with the goal of achieving GRN secretion into CSF and broad uptake via the sortilin receptor.

Results We found that despite a global increase in GRN throughout many brain regions, overexpression of GRN using AAV9 resulted in dramatic and selective hippocampal toxicity and degeneration affecting both neurons and glia. Histologically, hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. Similar but less severe effects were observed in wildtype animals. AAV4-mediated GRN delivery similarly resulted in T cell infiltration as well as ependymal hypertrophy. AAV.eGFP-injected control animals were not affected using either serotype.

Conclusions These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response following GRN gene delivery. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression in relevant animal models prior to progressing to the clinic.

Authors/Disclosures
Defne Amado, MD, PhD (Univ of PA) PRESENTER	Dr. Amado has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leal Therapeutics. Dr. Amado has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx/Vyvgart. Dr. Amado has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Molecular Therapy. Dr. Amado has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Saltz Mongeluzzi & Bendesky P.C.. The institution of Dr. Amado has received research support from NIH/NINDS. The institution of Dr. Amado has received research support from Active Against ALS. The institution of Dr. Amado has received research support from ASGCT. Dr. Amado has received intellectual property interests from a discovery or technology relating to health care.
Julianne Rieders	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Eric Lancaster, MD, PhD (The University of Pennsylvania, Dept. of Neurology)	Dr. Lancaster has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for merck. Dr. Lancaster has received intellectual property interests from a discovery or technology relating to health care. Dr. Lancaster has received personal compensation in the range of $50,000-$99,999 for serving as a Expert and Witness with US Vaccine Injury Compensation Program.
Beverly Davidson, PhD (The Children's Hospital of Philadelphia)	No disclosure on file
Alice Chen-Plotkin, MD	Dr. Chen-Plotkin has received intellectual property interests from a discovery or technology relating to health care.

��ɫ��

��ɫ��