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Roberts JA, Varma VR, An Y, Varma S, Candia J, Fantoni G, Tiwari V, Anerillas C, Williamson A, Saito A, Loeffler T, Schilcher I, Moaddel R, Khadeer M, Lovett J, Tanaka T, Pletnikova O, Troncoso JC, Bennett DA, Albert MS, Yu K, Niu M, Haroutunian V, Zhang B, Peng J, Croteau DL, Resnick SM, Gorospe M, Bohr VA, Ferrucci L, Thambisetty M. A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets. Sci Adv. 2021 Nov 12;7(46):eabi8178. Epub 2021 Nov 10 PubMed.
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UT Health San Antonio/South Texas VA
The study by Roberts and colleagues was designed to identify differential protein expression in AD that may be relevant to preclinical stages or risk for developing AD later in life. The experimental design allowed the researchers to identify drug targets that may be relevant in early disease. This is important because it may allow for treatment prior to neurodegeneration and cognitive impairment.
The directionality differences in protein expression in YAPS versus ROS and BLSA have important implications for drug discovery and development. Future experiments are needed to determine if/how to appropriately modulate these pathways during different disease stages. A sub-analysis focused on APOe4 carriers could provide additional insights into age-associated changes important to disease progression to provide some initial clarity on this issue.
I find it interesting that dasatinib was identified in their drug screen. Our upcoming Phase 2 trial “SToMP-AD” will use a combination of dasatinib and quercetin as an approach to clear senescent cells from older adults with amnestic MCI/early AD. In 2015 Dr. Jim Kirkland’s group at the Mayo Clinic, Rochester, Minnesota, identified dasatinib as an agent that selectively clears senescent cells (Zhu et al., 2015). Broadly, we hypothesize that targeting biological aging processes, such as cellular senescence, may delay, prevent, or effectively treat age-associated diseases such as AD. Our trial, along with others, will test this approach.
Identifying dasatinib at the convergence of two independent drug screens, one focused on senescent cells and the other on AD pathogenesis, is an exciting finding that lends support to the overall strategy.
For SToMP-AD, we are using an intermittent dosing schedule that consists of six cycles of 100 mg dasatinib/day x two days followed by a 14-day no-treatment period. This is repeated six times (i.e., subjects receive 1,200 mg dasatinib across the 12-week treatment period). In contrast, an example of a cancer regime would be 140 mg daily for 12 weeks, i.e., patients receive 11,760 mg across the 12-week period. The total difference across 12 weeks is that cancer patients receive 9.8 times more dasatinib than we are using. I am not an oncologist, and while there may be different doses for different stages and types of cancer, the example I provided is FDA-approved for Philadelphia chromosome-positive acute lymphoblastic leukemia, and resistance to, or intolerance of, initial treatment.
References:
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. Epub 2015 Apr 22 PubMed.
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