Flash from the Lab 2025

Is that a LAM or a mouse?

Of the dozens of attempts to generate a mouse model of LAM or TSC kidney disease by researchers around the world, LAM researchers still lack a mouse model to study disease development and progression. After three years of tedious mouse genetics, we successfully generated two new mouse models! Remarkably, by 7 months of age, we found that by mutating the TSC2 gene (the primary cause of LAM and TSC) in the developing peripheral nervous system (model #1) leads to abnormal lung growths (lesions) only in female mice. While the lung lesions are not LAM, this mouse model provides a phenomenal new tool to understand why only women develop LAM and to assess the role of hormones in LAM. Both male and female mice developed cysts and lesions in the kidney that have similar characteristics to the kidney disease common in LAM and TSC patients. Over the next few years, we will study lung and kidney disease in both mouse models. This will include testing the impact of hormones, rapamycin and our new anti-LAM drugs in these mouse models. Moreover, we will study whether the immune system is compromised in the mice with abnormal lung growths.

Sleeping on the job: T cells in LAM

Over the course of the past 4 years, we gained a greater understanding of the interaction between T cells and LAM cells. T cells are an important part of the immune system, but, in the presence of LAM cells, they become inactive. We now wonder that if we activate the T cells, will they stop LAM progression vs. “sleeping on the job” and letting LAM progress. We identified the receptor on LAM cells that has this affect on T cells and this may be worth targeting with different drug strategies.

New Drugs identified for LAM

In a series of laborious experiments, we found that the Health Canada/FDA-approved drug SAHA (known clinically as Vorinostat) and two new RNA-based drugs (which we designed) dramatically shrink TSC tumours in mice. These experiments were done in direct comparison with high dose rapamycin (known clinically as Sirolimus) treatment. Critically, our drugs performed better than the standard of care and only treatment for LAM and TSC kidney disease, rapamycin.

Our goal is to determine whether any of these drugs meet the high bar required to perform a clinical trial, including the funding of the trial. Developing a clinical trial for a rare disease is not for the faint of heart. Our efforts will be:

• Patent our RNA-based drugs which could provide an avenue for funding clinical trials. Importantly, for investors / drug companies, these RNA-based drugs may target a variety of cancers in addition to LAM.
• Publish our latest studies which will provide the scientific basis for the clinical trials. We will submit a manuscript on the RNA-based drugs this summer.
• Verify that our drugs eradicate TSC tumours such that the tumours do not regrow or relapse following treatment cessation. We know that LAM and TSC kidney disease regrow quickly once a patient stops taking rapamycin.
• Determine whether these drugs are still efficacious when taken together with rapamycin. Because rapamycin promotes cell survival, previous candidate LAM drugs, developed by researchers around the world, have failed this test. However, if any of our drugs eradicate TSC tumours in mice receiving rapamycin treatment, then we could propose a clinical trial in which patients could continue rapamycin treatment during the trial. This would reduce the risk to patients and increase the chance of funding a clinical trial.
• Test the impact of these drugs on lung function in the mouse. SAHA is a toxic drug approved to treat patients with blood cancers. We do not know how either SAHA or our RNA-based drugs will affect patients with reduced lung capacity.

Easter is coming – but don’t put all of your eggs in one basket

In the “don’t put all your eggs in one basket” department, our McGill collaborator, Arnold Kristof, previously identified the “UT” pathway as being over-active in LAM cells, which suggested it could contribute to LAM disease progression. Arnold and Bill collaborated to publish the molecular basis of UT hyperactivity. Using the LAM cells developed in Bill’s lab, Arnold found that UT works on a pathway unaffected by rapamycin and showed that blocking UT slows LAM cell migration and kills LAM cells. This study shows that a drug effectively targeting UT could complement rapamycin therapy for LAM patients.

Kidneys are the new lungs

The mouse TSC tumour assay that we have used in our drug studies is the standard in the LAM and TSC fields. But these tumours grow much faster than human LAM or human kidney TSC lesions. Our human TSC mini-kidneys, which we published in 2022, exquisitely model TSC kidney disease. We have continued to improve this model to generate human kidney TSC disease in mice following transplantation. After 6 months of disease progression, we will treat the TSC kidney disease mice with our drug candidates and rapamycin to test their efficacy on human TSC disease.

Go LOL Team Go!

• Adrianna, a practicing nephrologist, received her PhD at the Ottawa kidney centre, joined our LAM/TSC team and was awarded a Kidney Foundation of Canada Fellowship (KRESCENT) to study LAM related kidney disease. She is contributing her nephrology experience to analyse our TSC/LAM mouse models and studying TSC kidney disease using the advanced mini kidney system she is developing with Eric in our lab. Adrianna and Bill received seed funding from the Ottawa Hospital to support developing new models of kidney disease.
• Alberto, a PhD student in Bill’s lab whose research led to the development of one of our RNA-based drugs, won numerous awards during the last year including the Ottawa Hospital Research Institute Best Oral Presentation, the International Society for Stem Cell Research (ISSCR) travel award, the ISSCR Abstract Merit award, and the Stem Cell Network International Travel award. Alberto and Eric will submit their research for publication this summer.
• Amber graduated with her PhD in chemical engineering from UofT (Molly’s lab) after her stunning work defining how LAM cells turn off immune T cells, pointing to the potential of immunotherapy for LAM. Amber is now a scientist at Parallel Bio – a Boston-based biotech company where she is using the skills she honed on her LAM project to develop personalized therapies that target the immune system. Amber published several papers during her PhD. Her most exciting findings, showing how LAM cells turn off T cells, is being submitted for publication with our clinical colleague and immunologist, Dr. Stephen Juvet.
• Arianna, PhD student in Molly’s lab, worked closely with Amber to study the role of immune cells on cancer cell invasion into the Shoichet lab’s gels. She is studying how cancer cell invasion is impacted by macrophages – another immune system cell type that fights disease. Arianna’s expertise in the gel formulations has been particularly important to fellow graduate student Chris.
• Chris, a PhD student in Molly’s lab, is investigating how lymphatic endothelial cells influence LAM cell invasion in hydrogels. Just as the name implies, the lymphatic system likely plays a role in lymphangioleiomyomatosis. Our hydrogels may uncover a new mechanism in invasion, providing us with a better understanding of disease progression.
• Ellis, a PhD student in Bill’s lab, has led our LAM/TSC mouse team (including Julien, Adrianna and Alberto). Ellis’ presentation received the Best Oral Presentation award at the 2024 University of Ottawa Cellular & Molecular Medicine Research Day.
• Bill joined The LAM Foundation Scientific Advisory Board and will present his LAM/TSC research at the TSC International Research Conference in Maryland in June and at the LAM Foundation International Research Conference and LAMposium in Kansas City in September.
• Molly joined the Board of the Stem Cell Network, which funds research across Canada in stem cell biology, and serves on the Board of MaRS – one of the largest tech incubators in North America. She leads the Precision Medicine initiative at the University of Toronto, where she co-hosted the Trajectory to Translation in Women’s Health symposium. She also leads BioHubNet – the biomanufacturing training network – a cross-cutting network across Ontario and Canada. Molly loves spinning off companies from her lab and is eager to help Bill launch one out of his based on LAM.
• We are grateful for your continued and unwavering support! Our research would stagnate without your support. Research is the soil from which inventions sprout made and companies grow. The new US administration cancelled the TSC research grant program which previously funded some of Bill’s LAM research, closing an important funding mechanism. Now, more than ever, your support is critical to advancing knowledge out of the lab. Thank you! Thank you! Thank you for your support!