CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease
Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s di...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Alan J. Lerner [verfasserIn] Steven E. Arnold [verfasserIn] Erin Maxfield [verfasserIn] Aaron Koenig [verfasserIn] Maria E. Toth [verfasserIn] Brooke Fortin [verfasserIn] Natalia Mast [verfasserIn] Bianca A. Trombetta [verfasserIn] John Denker [verfasserIn] Andrew A. Pieper [verfasserIn] Curtis Tatsuoka [verfasserIn] Sangeetha Raghupathy [verfasserIn] Irina A. Pikuleva [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: Alzheimer’s Research & Therapy - BMC, 2015, 14(2022), 1, Seite 10 |
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| Übergeordnetes Werk: |
volume:14 ; year:2022 ; number:1 ; pages:10 |
| Links: |
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| DOI / URN: |
10.1186/s13195-022-01151-z |
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| Katalog-ID: |
DOAJ000812498 |
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| 520 | |a Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. | ||
| 650 | 4 | |a CYP46A1 | |
| 650 | 4 | |a Efavirenz | |
| 650 | 4 | |a Alzheimer’s disease | |
| 650 | 4 | |a 24-Hydroxycholesterol | |
| 650 | 4 | |a Stable isotope labeling kinetics | |
| 653 | 0 | |a Neurosciences. Biological psychiatry. Neuropsychiatry | |
| 653 | 0 | |a Neurology. Diseases of the nervous system | |
| 700 | 0 | |a Steven E. Arnold |e verfasserin |4 aut | |
| 700 | 0 | |a Erin Maxfield |e verfasserin |4 aut | |
| 700 | 0 | |a Aaron Koenig |e verfasserin |4 aut | |
| 700 | 0 | |a Maria E. Toth |e verfasserin |4 aut | |
| 700 | 0 | |a Brooke Fortin |e verfasserin |4 aut | |
| 700 | 0 | |a Natalia Mast |e verfasserin |4 aut | |
| 700 | 0 | |a Bianca A. Trombetta |e verfasserin |4 aut | |
| 700 | 0 | |a John Denker |e verfasserin |4 aut | |
| 700 | 0 | |a Andrew A. Pieper |e verfasserin |4 aut | |
| 700 | 0 | |a Curtis Tatsuoka |e verfasserin |4 aut | |
| 700 | 0 | |a Sangeetha Raghupathy |e verfasserin |4 aut | |
| 700 | 0 | |a Irina A. Pikuleva |e verfasserin |4 aut | |
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10.1186/s13195-022-01151-z doi (DE-627)DOAJ000812498 (DE-599)DOAJbe51f0c921904c6eb9b8ba7aa6a50ed7 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Alan J. Lerner verfasserin aut CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Steven E. Arnold verfasserin aut Erin Maxfield verfasserin aut Aaron Koenig verfasserin aut Maria E. Toth verfasserin aut Brooke Fortin verfasserin aut Natalia Mast verfasserin aut Bianca A. Trombetta verfasserin aut John Denker verfasserin aut Andrew A. Pieper verfasserin aut Curtis Tatsuoka verfasserin aut Sangeetha Raghupathy verfasserin aut Irina A. Pikuleva verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 14(2022), 1, Seite 10 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:14 year:2022 number:1 pages:10 https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/article/be51f0c921904c6eb9b8ba7aa6a50ed7 kostenfrei https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 10 |
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10.1186/s13195-022-01151-z doi (DE-627)DOAJ000812498 (DE-599)DOAJbe51f0c921904c6eb9b8ba7aa6a50ed7 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Alan J. Lerner verfasserin aut CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Steven E. Arnold verfasserin aut Erin Maxfield verfasserin aut Aaron Koenig verfasserin aut Maria E. Toth verfasserin aut Brooke Fortin verfasserin aut Natalia Mast verfasserin aut Bianca A. Trombetta verfasserin aut John Denker verfasserin aut Andrew A. Pieper verfasserin aut Curtis Tatsuoka verfasserin aut Sangeetha Raghupathy verfasserin aut Irina A. Pikuleva verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 14(2022), 1, Seite 10 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:14 year:2022 number:1 pages:10 https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/article/be51f0c921904c6eb9b8ba7aa6a50ed7 kostenfrei https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 10 |
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10.1186/s13195-022-01151-z doi (DE-627)DOAJ000812498 (DE-599)DOAJbe51f0c921904c6eb9b8ba7aa6a50ed7 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Alan J. Lerner verfasserin aut CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Steven E. Arnold verfasserin aut Erin Maxfield verfasserin aut Aaron Koenig verfasserin aut Maria E. Toth verfasserin aut Brooke Fortin verfasserin aut Natalia Mast verfasserin aut Bianca A. Trombetta verfasserin aut John Denker verfasserin aut Andrew A. Pieper verfasserin aut Curtis Tatsuoka verfasserin aut Sangeetha Raghupathy verfasserin aut Irina A. Pikuleva verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 14(2022), 1, Seite 10 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:14 year:2022 number:1 pages:10 https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/article/be51f0c921904c6eb9b8ba7aa6a50ed7 kostenfrei https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 10 |
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10.1186/s13195-022-01151-z doi (DE-627)DOAJ000812498 (DE-599)DOAJbe51f0c921904c6eb9b8ba7aa6a50ed7 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Alan J. Lerner verfasserin aut CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Steven E. Arnold verfasserin aut Erin Maxfield verfasserin aut Aaron Koenig verfasserin aut Maria E. Toth verfasserin aut Brooke Fortin verfasserin aut Natalia Mast verfasserin aut Bianca A. Trombetta verfasserin aut John Denker verfasserin aut Andrew A. Pieper verfasserin aut Curtis Tatsuoka verfasserin aut Sangeetha Raghupathy verfasserin aut Irina A. Pikuleva verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 14(2022), 1, Seite 10 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:14 year:2022 number:1 pages:10 https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/article/be51f0c921904c6eb9b8ba7aa6a50ed7 kostenfrei https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 10 |
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10.1186/s13195-022-01151-z doi (DE-627)DOAJ000812498 (DE-599)DOAJbe51f0c921904c6eb9b8ba7aa6a50ed7 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Alan J. Lerner verfasserin aut CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Steven E. Arnold verfasserin aut Erin Maxfield verfasserin aut Aaron Koenig verfasserin aut Maria E. Toth verfasserin aut Brooke Fortin verfasserin aut Natalia Mast verfasserin aut Bianca A. Trombetta verfasserin aut John Denker verfasserin aut Andrew A. Pieper verfasserin aut Curtis Tatsuoka verfasserin aut Sangeetha Raghupathy verfasserin aut Irina A. Pikuleva verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 14(2022), 1, Seite 10 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:14 year:2022 number:1 pages:10 https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/article/be51f0c921904c6eb9b8ba7aa6a50ed7 kostenfrei https://doi.org/10.1186/s13195-022-01151-z kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 10 |
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Alan J. Lerner Steven E. Arnold Erin Maxfield Aaron Koenig Maria E. Toth Brooke Fortin Natalia Mast Bianca A. Trombetta John Denker Andrew A. Pieper Curtis Tatsuoka Sangeetha Raghupathy Irina A. Pikuleva |
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CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
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Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. |
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Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. |
| abstract_unstemmed |
Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. |
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