Safety and Efficacy of Injectable Klotho Plasmid Gene Therapy in Humans

Summary

The purpose of this study is to investigate the safety and efficacy of a gene therapy for Klotho, delivered via a nonviral plasmid in healthy adult volunteers. Additionally, this study seeks to understand the cognitive and health benefits of the Klotho gene therapy.

Timeline

Start

2025-10-06

Primary completion

2026-08

Completion

2026-08

Publications

• Background Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006 Dec 7;444(7120):770-4. doi: 10.1038/nature05315. Epub 2006 Oct 29.
• Background Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998 Jan 26;242(3):626-30. doi: 10.1006/bbrc.1997.8019.
• Background Masso A, Sanchez A, Bosch A, Gimenez-Llort L, Chillon M. Secreted alphaKlotho isoform protects against age-dependent memory deficits. Mol Psychiatry. 2018 Sep;23(9):1937-1947. doi: 10.1038/mp.2017.211. Epub 2017 Oct 31.
• Background Masso A, Sanchez A, Gimenez-Llort L, Lizcano JM, Canete M, Garcia B, Torres-Lista V, Puig M, Bosch A, Chillon M. Secreted and Transmembrane alphaKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression. PLoS One. 2015 Nov 24;10(11):e0143623. doi: 10.1371/journal.pone.0143623. eCollection 2015.
• Background Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. alpha-Klotho as a regulator of calcium homeostasis. Science. 2007 Jun 15;316(5831):1615-8. doi: 10.1126/science.1135901.
• Background Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997 Nov 6;390(6655):45-51. doi: 10.1038/36285.
• Background Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 2004 May 7;565(1-3):143-7. doi: 10.1016/j.febslet.2004.03.090.
• Background Gupta S, Moreno AJ, Wang D, Leon J, Chen C, Hahn O, Poon Y, Greenberg K, David N, Wyss-Coray T, Raftery D, Promislow DEL, Dubal DB. KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice. J Neurosci. 2022 May 11;42(19):4016-4025. doi: 10.1523/JNEUROSCI.2458-21.2022. Epub 2022 Apr 15.
• Background Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Life extension factor klotho enhances cognition. Cell Rep. 2014 May 22;7(4):1065-76. doi: 10.1016/j.celrep.2014.03.076. Epub 2014 May 10.
• Background Davidsohn N, Pezone M, Vernet A, Graveline A, Oliver D, Slomovic S, Punthambaker S, Sun X, Liao R, Bonventre JV, Church GM. A single combination gene therapy treats multiple age-related diseases. Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23505-23511. doi: 10.1073/pnas.1910073116. Epub 2019 Nov 4.
• Background Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19796-801. doi: 10.1073/pnas.0709805104. Epub 2007 Dec 3.
• Background Castner SA, Gupta S, Wang D, Moreno AJ, Park C, Chen C, Poon Y, Groen A, Greenberg K, David N, Boone T, Baxter MG, Williams GV, Dubal DB. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging. 2023 Aug;3(8):931-937. doi: 10.1038/s43587-023-00441-x. Epub 2023 Jul 3.
• Background Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):856-61. doi: 10.1073/pnas.022484299. Epub 2002 Jan 15.
• Background Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Klotho Is a Neuroprotective and Cognition-Enhancing Protein. Vitam Horm. 2016;101:215-38. doi: 10.1016/bs.vh.2016.02.004. Epub 2016 Mar 22.

Drugs

Indications

No indication recorded.