好色先生

好色先生

Explore the latest content from across our publications

Log In

Forgot Password?
Create New Account

Loading... please wait

Abstract Details

AAV-Mediated Progranulin Delivery to a Mouse Model of FTD/CNL Causes T Cell-Mediated Toxicity
Aging, Dementia, and Behavioral Neurology
S9 - Aging and Dementia: Clinical Trials and Novel Therapies (4:14 PM-4:25 PM)
005

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.

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. 
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.
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.
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 $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. 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.