Synergistic efficacy by combination of AUTOTAC and low dose radiation in Alzheimer’s disease
Jae Sik Kim,
Korea Republic of
PO-1821
Abstract
Synergistic efficacy by combination of AUTOTAC and low dose radiation in Alzheimer’s disease
Authors: Jae Sik Kim1, Su Hyun Lee2, Eul-Bee Ko3, Sung Hyun Kim3, Ki Woon Sung2, Chang Hoon Ji2, Minho Moon4, Yong Tae Kwon2, Weon Kuu Chung5
1Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Department of Radiation Oncology, Seoul, Korea Republic of; 2College of Medicine, Seoul National University, Cellular Degradation Biology Research Center and Department of Biomedical Sciences, Seoul , Korea Republic of; 3AUTOTAC Inc, AUTOTAC Inc, Seoul , Korea Republic of; 4College of Medicine, Konyang University, Department of Biochemistry, Daejeon, Korea Republic of; 5Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Department of Radiation Oncology, Seoul , Korea Republic of
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Purpose or Objective
The
neuropathological features of Alzheimer’s disease (AD) include the accumulation
of amyloid-β (Aβ) and hyperphosphorylated tau aggregates. Recently, low-dose
ionizing radiation (LDIR) has emerged as a promising therapeutic approach for
AD. This modality is currently being evaluated in clinical trials for patients
with the neurologic disorder. To enhance the efficacy of LDIR, we employed the AUTOphagy-TArgeting
Chimera (AUTOTAC) technology in combination with LDIR.
Material and Methods
AUTOTAC
utilizes bifunctional molecules composed of target-binding ligands (TBLs)
linked to autophagy-targeting ligand (ATLs). The synergistic efficacy of AUTOTAC
and LDIR was validated using 11-month-old 5X FAD mice that accumulate
extracellular Aβ plaques in the brain. The mice received fractionated therapy
at 300 cGy (60 cGy per fraction for five times, radiation therapy regimen given
over three weeks) and injected with the AUTOTAC compound ACT-108 (10 mg per
kilogram, three times per week) that was demonstrated to eradicate
intracellular phospho-tau aggregates from murine brains.
Results
The
combination treatment significantly improved the behavior as compared with the
radiation alone treatment (p*=
0.0223) or ACT-108 alone treatment (p***=
0.0009). In addition, the combination treatment group also improved the cognition
(p*=0.0458) as compared with the
radiation alone treatment group (p=
0.7178) or ACT-108 alone treatment group (p=
0.7889).
Conclusion
These results provide a possibility that
extracellular Aβ plaques may be degraded through the combinational treatment of
AUTOTAC and LDIR.