Sirolimus for Brain Health

Overseen By Jenn Cornelius-Green

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Missouri-Columbia

Must not be taking: Antiplatelets, Anticoagulants, Immunosuppressants, others

Disqualifiers: Diabetes, Pulmonary disease, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

205 Participants Needed

Trial Summary

What is the purpose of this trial?

Alzheimer's disease is a devastating neurodegenerative disease characterized by accumulation of clumps (also called plaques) and bundles of fibers (also called tangles) in the brain, for which there is currently no cure. Sirolimus is an FDA-approved medication which may improve the blood flow to the brain. Part I: This study is designed to see if sirolimus treatment improves MRI blood flow to the brain in individuals with and without a genetic predisposition to Alzheimer's disease. Part I of this study is complete and no longer enrolling participants. Part II: Ongoing research will expand the genetic predisposition cohort and further explore the drug's impact on the lung perfusion via hyperpolarized xenon-129 gas MRI and the brain-vascular connection. Only subjects who are APOE4 carriers will be enrolled in Part II. Hyperpolarized xenon-129 gas MRI is a non-invasive technique in which a subject inhales a bolus of hyperpolarized xenon-129 gas which can be directly imaged by the MRI as it physiologically distributes itself throughout the lung interior and within tissue and red blood cells. It thus allows for direct imaging and quantification of regional lung function: ventilation, gas-exchange, and perfusion. The relationship between pulmonary vascular function and brain perfusion is largely unstudied. We hope to investigate the relationship between pulmonary vascular function and cerebral blood flow by quantifying both lung and brain perfusion before and after the administration of Sirolimus.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically those that affect cytochrome P450 3A4 (CYP3A4) and anti-platelet or anti-coagulant medications other than aspirin. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Sirolimus for brain health?

Sirolimus, known for its role in preventing organ rejection, has shown potential in treating skin conditions and extending lifespan in animal studies, suggesting it may have broader health benefits. However, there is no direct evidence from the provided research specifically supporting its effectiveness for brain health. ^{1 2 3 4 5}

Is sirolimus generally safe for human use?

Sirolimus, also known as Rapamune, is generally considered safe for human use, especially in preventing organ rejection in kidney transplant patients. It has a lower risk of kidney, nerve, and certain blood-related complications compared to other similar drugs. However, it can cause side effects like mouth sores, especially at higher doses. ^{3 5 6 7 8}

How is the drug sirolimus unique for brain health?

Sirolimus is unique because it works by inhibiting a protein called mTOR, which is involved in cell growth and metabolism, and has shown potential in treating cognitive dysfunction, such as in Alzheimer's disease. Unlike other treatments, it has anti-aging properties and is being explored for its ability to improve brain health by affecting pathways related to aging and cognitive decline. ^{3 4 5 8 9}

Research Team

Ai-Ling Lin, PhD

Principal Investigator

University of Missouri-Columbia

Eligibility Criteria

This trial is for healthy adults aged 45-65 with good cognitive health, as shown by MoCA and CDR scores. It's open to all ethnic groups and includes those genetically predisposed to Alzheimer's (carriers of the APOE4 gene) and those who are not. People with liver or kidney disease, high BMI, diabetes, recent cancer treatments, certain heart conditions, or on medications affecting CYP3A4 can't participate.

Inclusion Criteria

Clinical Dementia Rating (CDR) Staging Instrument = 0

I carry one or two copies of the APOE4 gene.

I am between 45 and 65 years old.

Exclusion Criteria

Untreated hypertriglyceridemia (fasting triglycerides < 300 mg/dl)

Likelihood of claustrophobia

BMI ≥35 (based on MRI feasibility)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Sirolimus treatment to assess its impact on cerebral blood flow and lung perfusion

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Sirolimus

Trial Overview The study tests whether Sirolimus can improve brain blood flow in individuals at risk for Alzheimer's. Participants will be given Sirolimus and undergo MRI scans to assess changes in cerebral blood flow related to their genetic risk for Alzheimer’s disease.

Participant Groups

Group I: Non-Carrier APOE4 Experimental Treatment 1 Intervention

Group II: Carrier APOE4 Experimental Treatment 1 Intervention

Sirolimus is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in European Union as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Canada as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Japan as Rapamune for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

University of Missouri-Columbia

Lead Sponsor

Trials

387

Recruited

629,000+

Findings from Research

Rapamune (Sirolimus) is an important immunosuppressant used in solid organ transplants for various purposes, including induction therapy and managing refractory rejection.

Understanding the pharmacodynamics and side effects of Rapamune is crucial for critical care nurses to enhance patient education and improve outcomes in transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on transplant pharmacology: sirolimus. Hoffmann, RL., Roesch, T.[2021]

In a study of 313 heart transplant recipients, switching from cyclosporine to sirolimus did not lead to any cases of stroke or transient ischemic attacks, suggesting a favorable safety profile for sirolimus in this high-risk population.

While sirolimus was associated with a higher hazard ratio for neurologic events like tremor and depression, it did not result in major neurotoxicity, indicating that sirolimus may be a safer immunosuppressant option compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No major neurologic complications with sirolimus use in heart transplant recipients. van de Beek, D., Kremers, WK., Kushwaha, SS., et al.[2022]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Sirolimus is an effective immunosuppressive drug with a long half-life and significant interpatient variability in its pharmacokinetics, which can be influenced by other medications like prednisone and cyclosporine.

Higher doses of sirolimus are associated with a decreased risk of organ rejection, although the clinical significance of its metabolites is still unclear and requires further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and metabolism of sirolimus. Gallant-Haidner, HL., Trepanier, DJ., Freitag, DG., et al.[2019]

A systematic review of 9 studies involving 575 pediatric patients indicates that oral sirolimus is generally safe for treating childhood diseases, with oral mucositis being the most common adverse event reported in 8.2% of cases.

Adverse events were significantly more frequent in patients with higher sirolimus concentrations (≥10 ng/mL), highlighting the importance of monitoring drug levels to minimize serious side effects, especially in children with vascular anomalies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review. Zhang, Z., Li, Y., Zhang, G., et al.[2023]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

Sirolimus has been shown to reverse cognitive dysfunction in a rat model induced by scopolamine, suggesting its potential as a therapeutic agent for Alzheimer's disease.

The study indicates that the therapeutic effects of sirolimus are likely linked to the activation of autophagy, as evidenced by changes in amyloid-β levels and other markers in the brain regions associated with cognition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

3-methyladenine, an autophagic inhibitor, attenuates therapeutic effects of sirolimus on scopolamine-induced cognitive dysfunction in a rat model. Zhu, B., Yang, C., Ding, LC., et al.[2020]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Update on transplant pharmacology: sirolimus. [2021]

2. England pubmed.ncbi.nlm.nih.gov

No major neurologic complications with sirolimus use in heart transplant recipients. [2022]

3. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

4. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and metabolism of sirolimus. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review. [2023]

7. Denmark pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

3-methyladenine, an autophagic inhibitor, attenuates therapeutic effects of sirolimus on scopolamine-induced cognitive dysfunction in a rat model. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]