Safety and Efficacy of Injectable Klotho Plasmid Gene Therapy in Humans

Official title

Evaluating the Safety and Efficacy of Injectable Klotho Plasmid Gene Therapy in Humans: An Interventional, Non-Placebo-Controlled Pilot Phase Study

Overview

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.

Detailed description

Note that the investigational product will be administered at a site outside of the U.S. which is not under FDA jurisdiction, and only non-treatment pre/post outcome assessments (e.g., cognitive assessments or blood sample collection) occur at the U.S. site.

Participants will take part in cognitive and health testing before and after administration of plasmid-delivered Klotho gene therapy. The method of administration will be subcutaneous injection into abdominal fat deposits. Klotho may improve cognitive function, kidney function, healthspan, and lifespan. Healthy volunteers will partake in a series of blood draws, health screenings, questionnaires, brain perfusion/function measures, and cognitive testing multiple times before and after the intervention.

Interventions

• Genetic Injectable Plasmid Klotho Gene Therapy
  Injection of plasmid-delivered Klotho gene therapy

Primary outcome measures

• Concentration of Serum α-Klotho Measured by Enzyme-Linked Immunosorbent Assay (pg/mL) [Time frame: Measured 1 month before and 7 days before injection, then 3 days, 7 days, 1 month, 3 months, 6 months after]
• Adverse Events: Number and Percentage of Participants Experiencing Treatment-Emergent Adverse Events as Assessed Patient-Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) [Time frame: Measured 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum Fibroblast Growth Factor 23 (FGF23) Measured by Enzyme-Linked Immunosorbent Assay (pg/mL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Intact Parathyroid Hormone Measured by Two-Site Immunoassay (pg/mL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum 1,25-Dihydroxyvitamin D (Calcitriol) Measured by Liquid Chromatography-Tandem Mass Spectrometry (pg/mL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum Phosphorus Measured by Clinical Chemistry Analyzer (mg/dL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Urinary Phosphate Excretion Measured by Clinical Chemistry Assay (mg/24 h or mg/g Creatinine) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum Cystatin C Measured by Immunoassay (mg/L) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]

Secondary outcome measures (12)

• Change From Baseline in World Health Organization Quality of Life Brief Version Domain Scores (0-100) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 month, 6 months after.]
• Change From Baseline in Flanker Inhibitory Control and Attention Test T-Score (Mean 50 ± 10) [Time frame: Measured 7 days before, then 3 days, 7 days, 1 month, 3 months, 6 months after treatment.]
• Change From Baseline in Dimensional Change Card Sort Test T-Score (Mean 50 ± 10) [Time frame: Measured 7 days before, then 3 days, 7 days, 1 month, 3 months, 6 months after treatment.]
• Change From Baseline in Pattern Comparison Processing Speed Test T-Score (Mean 50 ± 10) [Time frame: Measured 7 days before, then 3 days, 7 days, 1 month, 3 months, 6 months after treatment.]
• Change From Baseline in Picture Sequence Memory Test T-Score, Forms A and B (Mean 50 ± 10) [Time frame: Measured 7 days before, then 3 days, 7 days, 1 month, 3 months, 6 months after treatment.]
• Change From Baseline in Picture Vocabulary Test T-Score (Mean 50 ± 10) [Time frame: Measured 7 days before, then 3 days, 7 days, 1 month, 3 months, 6 months after treatment.]
• Change From Baseline in Reynolds Intellectual Assessment Scales-Second Edition (RIAS-2) Composite Scores (Standard Score Mean 100 ± 15) [Time frame: Measured 1 month before and then 1 month and 3 months after.]
• Concentration of Serum Glucose Measured by Clinical Chemistry Analyzer (mg/dL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Total Serum Calcium Measured by Clinical Chemistry Analyzer (mg/dL) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Ionized Calcium Measured by Ion-Selective Electrode (mmol/L) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum Sodium Measured by Ion-Selective Electrode (mmol/L) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]
• Concentration of Serum Potassium Measured by Ion-Selective Electrode (mmol/L) [Time frame: Measured 1 month before, 7 days before, and then 3 days, 7 days, 1 month, 3 months, and 6 months after treatment.]

Eligibility criteria

Inclusion criteria

• Participant is open to morphological change
• If female, participant agrees to maintain contraception
• If female, participant agrees to take a pregnancy test
• If female, participant agrees to a pregnancy waiver

Exclusion criteria

• Women of childbearing potential who are unwilling or unable to use effective contraception for the duration of the study
• History of cancer diagnosis
• Preexisting medical issues that may be exacerbated by the treatment
• Has received any gene therapy within the past 12 months
• Unwilling or unable to provide written informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 1 center

• Apeiron Center — Austin

Honduras · 1 center

• GARM Clinic — Roatán

Publications

• 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. PMID 17086194
• 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. PMID 9464267
• 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. PMID 29086766
• 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. PMID 26599613
• 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. PMID 17569864
• 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. PMID 9363890
• 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. PMID 15135068
• 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. PMID 35428698

Identifiers

NCT: NCT07216781 · MINICIRCLE-KLO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗