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Project Summary:
A double blinded randomized controlled pilot clinical trial to determine if low-dose rapamycin can improve symptoms in patients with long COVID. The trial will be performed at the Cohn Center for Recovery from Complex Chronic Illness at Mount Sinai. Blood samples obtained from clinical trial participants will be analyzed by Akiko Iwasaki and team at Yale University to measure immune parameters changes potentially associated with rapamycin use.
Project Background:
Rapamycin (Sirolimus) is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which regulates immune and growth- inhibitory signaling. Preclinical studies of rapamycin – an FDA- approved, generic drug – have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. The dose of rapamycin used for lifespan extension is much lower than that used for rapamycin’s conventional use as an organ transplant rejection or cancer therapy drug.
Increasingly, rapamycin is also being trialed or prescribed in a low, once-weekly dose in an effort to improve immune function and/or disease progression in conditions tied to microbial or viral infection. It follows that low-dose rapamycin may benefit patients with long COVID. More specifically, long COVID is increasingly connected to persistence of the SARS-CoV-2 RNA or protein in tissue, Epstein-Barr virus reactivation, and T cell exhaustion. At certain doses and delivery schedules, rapamycin or related mTOR inhibitors have been shown to have antiviral properties and the ability to boost at least some aspects of immune function. For example, two studies found that low-dose mTOR inhibiting rapalogs increased interferon-induced antiviral gene expression. Interferons are the first line of defense against viruses and induce the expression of hundreds of antiviral genes that inhibit the actions of many different viruses.
With such effects in mind, one clinical trial found that continuous rapamycin use throughout the SARS-CoV-2 infection period was associated with a significant reduction in moderate or severe COVID-19 cases. Rapamycin users also did not report any cases of long COVID, despite being an average of 7.5 years older than non-users. In another study, once-weekly dosing of the rapalog mTOR inhibitor Everolimus (RAD001) at 5 mg/week for 6 weeks was found to boost influenza vaccine immune response in otherwise healthy older adults without significant side effects. Indeed, in the study, RAD001 was shown to reduce the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, a marker of T cell exhaustion.
Rapamycin has not been shown to induce side effects at lower doses used in anti-aging or immune modulating trials. For example, this clinical trial of rapamycin to extend the lifespan (average dose was 6 mg) found no evidence for significant increases in health risks, other than mouth sores in 15% of subjects (compared to 5% of controls) from rapamycin use. The sores were typically mild, similar to canker sores, and different from the severe mouth sores experienced by organ transplant patients taking high doses of rapamycin and other strong immune suppressants. Importantly, no obvious difference in risk of infection was apparent between groups. Indeed, in one study the rapalog RTB101 was shown to decrease the incidence of respiratory tract infections in older adults.
Link
A double blinded randomized controlled pilot clinical trial to determine if low-dose rapamycin can improve symptoms in patients with long COVID. The trial will be performed at the Cohn Center for Recovery from Complex Chronic Illness at Mount Sinai. Blood samples obtained from clinical trial participants will be analyzed by Akiko Iwasaki and team at Yale University to measure immune parameters changes potentially associated with rapamycin use.
Project Background:
Rapamycin (Sirolimus) is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which regulates immune and growth- inhibitory signaling. Preclinical studies of rapamycin – an FDA- approved, generic drug – have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. The dose of rapamycin used for lifespan extension is much lower than that used for rapamycin’s conventional use as an organ transplant rejection or cancer therapy drug.
Increasingly, rapamycin is also being trialed or prescribed in a low, once-weekly dose in an effort to improve immune function and/or disease progression in conditions tied to microbial or viral infection. It follows that low-dose rapamycin may benefit patients with long COVID. More specifically, long COVID is increasingly connected to persistence of the SARS-CoV-2 RNA or protein in tissue, Epstein-Barr virus reactivation, and T cell exhaustion. At certain doses and delivery schedules, rapamycin or related mTOR inhibitors have been shown to have antiviral properties and the ability to boost at least some aspects of immune function. For example, two studies found that low-dose mTOR inhibiting rapalogs increased interferon-induced antiviral gene expression. Interferons are the first line of defense against viruses and induce the expression of hundreds of antiviral genes that inhibit the actions of many different viruses.
With such effects in mind, one clinical trial found that continuous rapamycin use throughout the SARS-CoV-2 infection period was associated with a significant reduction in moderate or severe COVID-19 cases. Rapamycin users also did not report any cases of long COVID, despite being an average of 7.5 years older than non-users. In another study, once-weekly dosing of the rapalog mTOR inhibitor Everolimus (RAD001) at 5 mg/week for 6 weeks was found to boost influenza vaccine immune response in otherwise healthy older adults without significant side effects. Indeed, in the study, RAD001 was shown to reduce the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, a marker of T cell exhaustion.
Rapamycin has not been shown to induce side effects at lower doses used in anti-aging or immune modulating trials. For example, this clinical trial of rapamycin to extend the lifespan (average dose was 6 mg) found no evidence for significant increases in health risks, other than mouth sores in 15% of subjects (compared to 5% of controls) from rapamycin use. The sores were typically mild, similar to canker sores, and different from the severe mouth sores experienced by organ transplant patients taking high doses of rapamycin and other strong immune suppressants. Importantly, no obvious difference in risk of infection was apparent between groups. Indeed, in one study the rapalog RTB101 was shown to decrease the incidence of respiratory tract infections in older adults.
Link
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