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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests sirolimus (Rapamune) to determine if it can improve blood flow to the brain, potentially benefiting those with Alzheimer's disease, a condition that damages the brain over time. The trial employs a special MRI technique to examine the drug's effects on both lung and brain blood flow. Currently, it seeks participants who carry the APOE4 gene, associated with a higher risk of Alzheimer's. Interested individuals should not have severe lung issues or require supplemental oxygen. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that sirolimus is likely to be safe for humans?

Research shows that sirolimus, the treatment under study, is generally well-tolerated. One study found that patients taking sirolimus had a slightly higher chance of experiencing neurological or psychiatric issues, but these events were rare, and the risk was low. Another study indicated that a standard 2 mg dose of sirolimus is safer than a higher 5 mg dose, suggesting the lower dose is safer for most people.

Sirolimus is already FDA-approved for other uses, meaning it has undergone safety testing. Most safety information comes from patients with serious health conditions, such as organ transplant recipients. Research also shows that long-term use of sirolimus does not affect children's growth or cause major liver or blood problems.

While sirolimus is being tested for Alzheimer's disease in this study, current data suggests it is generally safe. However, discussing any concerns or questions with a healthcare provider before joining a clinical trial is always important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Sirolimus is unique because it targets brain health in a way that differs from most current treatments, which often focus on managing symptoms or slowing progression. Sirolimus uses a distinct mechanism by inhibiting the mTOR pathway, which plays a crucial role in cell growth and survival. This approach could potentially protect brain cells and improve cognitive function. Researchers are excited about Sirolimus because it offers a novel way to address underlying brain health issues, potentially leading to better outcomes than traditional therapies.

What evidence suggests that Sirolimus might be an effective treatment for Alzheimer's disease?

Research has shown that sirolimus, also known as rapamycin, may aid in treating Alzheimer's disease. Studies in mice have found that sirolimus can prevent or even reverse memory and thinking problems associated with Alzheimer's. It may achieve this by reversing brain changes caused by the disease. Additionally, sirolimus appears to enhance blood vessel function in the brain, which is crucial for brain health. While these animal results are promising, more human studies are needed to confirm these effects. In this trial, researchers will divide participants into two groups based on their APOE4 carrier status to evaluate sirolimus's effects on brain health. ^{6 7 8 9 10}

Who Is on the Research Team?

Ai-Ling Lin, PhD

Principal Investigator

University of Missouri-Columbia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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 (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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12092812/

Rapamycin treatment for Alzheimer's disease and related ... The drug rapamycin has been shown to increase longevity and reverse changes in the brain associated with Alzheimer's disease and related ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10993488/

Evaluating the effect of rapamycin treatment in Alzheimer's ... Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02042326

Study Details | NCT02042326 | Prospective Evaluation of ... The aim of the study is to evaluate the efficacy and safety of sirolimus (oral form), to decrease the volume and symptoms due to superficial arteriovenous ...

4. alzdiscovery.org alzdiscovery.org/uploads/cognitive_vitality_media/Rapamycin-Cognitive-Vitality-For-Researchers.pdf

Rapamycin (and rapalogs) Secondary outcomes include the BBB penetrance of rapamycin, cognitive outcomes (PACC5, CDR-SoB), functional status (activities of daily living, gait speed, grip.

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/11/NCT04200911/Prot_SAP_000.pdf

Cognition, Age, and RaPamycin Effectiveness record data (UT Health EPIC, UHS Sunrise) including pre-existing history ... Chronic rapamycin restores brain vascular integrity and function through ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2665977/

No Major Neurologic Complications With Sirolimus Use in ... The hazard ratio of sirolimus for any neurologic or psychiatric event was 1.94 (95% confidence interval, 0.67-4.29). This hazard ratio was driven mainly by the ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf

RAPAMUNE (sirolimus) Label - accessdata.fda.gov Patients receiving 2 mg of Rapamune Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of. Rapamune Oral ...

8. nature.com nature.com/articles/s43856-025-00904-9

Rapamycin treatment for Alzheimer's disease and related ... However, most safety data have been collected from adults with other serious medical conditions, often following solid organ transplantation.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11325711/

Long-term safety and influence on growth in patients ... Sirolimus's long-term administration is not associated with adverse effects on children's physical growth, nor significant alterations in hematopoietic, liver, ...

10. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-sirolimus-for-treating-high-grade-glioma-in-children/

Study on the Safety and Effectiveness of Sirolimus ... Rapamycin is a medication being studied for its safety and effectiveness in treating high-grade gliomas, which are a type of brain tumor, in ...