Develop innovative sex-selective diagnostic tools and therapies that translate discoveries of sex differences in medicine to enhance efficacy and precision medicine.
ICON-✗ is translating discoveries about sex differences in medicine into more effective diagnostic tools and therapeutics for both men and women. We believe that targeting causes early in development in a sex-dependent way will attenuate disability and prevent illness later in life. Some initial examples of ongoing work are presented.
Development of patient-derived cellular models of brain disease
The Perlis Lab is focused on development of patient-derived cellular models of brain diseases, including by sex. In addition to work with induced pluripotent stem cells, they validated methods for generating microglia-like cells from peripheral blood (Sellgren et al, 2017), and more recently, from neonatal cord blood (Sheridan, Trans Psych 2021). They applied these methods to demonstrate abnormalities in models of microglia-mediated synaptic pruning (Sellgren et al, 2019). Since these models are highly scalable and amenable to high-throughput screening, they have subsequently applied them to identify small molecules and other perturbations that modulate microglia-mediated pruning (for a review, see Sheridan Biol Psych 2022).
An emerging area of investigation for the lab is the way in which male and female patient-derived microglia and other neural cells differ functionally. These differences may facilitate the identification of sex-specific or sex-dependent biomarkers and/or treatment strategies.
More on Roy Perlis
Development of Non-Implanted Neuromodulation Therapeutics
The co-occurrence of depression and CVD is a primary cause of disability worldwide. We currently have no effective therapeutics targeted specifically to treat this comorbidity. In a series of recent experiments, Ronald G. Garcia, M.D., Ph.D., Vitaly Napadow, Ph.D., Jill Goldstein, Ph.D. and colleagues are developing the therapeutic potential of a novel non-invasive stimulation of the vagus nerve (the primary electrical conduit between the brain, heart and gut) to regulate mood (alleviating depressed mood and anxiety) and cardiovascular function.
Respiratory-gated transcutaneous Vagus Nerve Stimulation (tVNS-called RAVANS) stimulates the auricular branch of the vagus nerve on the outer ear and synchronizes the electrical stimuli to variations in the person’s own respiratory rhythm to enhance its efficacy. Ultimately, we aim to improve brain health, cardiovascular, and metabolic function in a sex-dependent way using this non-invasive therapeutic. We are also expanding the use of RAVANS to target autoimmune disorders, such as rheumatoid arthritis. Plans are ongoing to develop RAVANS into a wearable system, partnering with Cala Health.
Maintaining Cardiovascular and Brain Health Postpartum: Early Intervention for Prevention
Amy Sarma, M.D., cardiologist and faculty in the MGH Corrigan-Minehan Women’s Heart Health Program (partnering with ICON-X), is improving outcomes in the postpartum period of pregnancies complicated by CVD and preeclampsia. Using novel cardiac digital health devices that mothers take home after birth, she is identifying clinical signals for hypertension risk postpartum, in order to treat women early. This unique strategy (in collaboration with the MassGeneralBrigham Digital Health Initiative) uses smart Bluetooth technology to send clinical signals back to their clinicians allowing for early intervention prior to manifestation of pathology to prevent readmission. ICON-✗ colleagues also intend to develop and apply other digital health tools to identify early signs of sex differences in depression and cognitive decline in high risk populations across the lifespan.
Novel Sex-Dependent Therapeutics for Major Depression
Women are more vulnerable to neuroinflammatory disorders including depression. Some of this is due to sex differences in how temperature-sensitive nerve cells and immune cells communicate, leading to more inflammation in women. Elevating the body temperature is a burgeoning treatment for depression that may tamp down inflammation in a sex-dependent manner, leading to better mood. In a bench-to-bedside approach, ICON-✗ collaborator, Simmie Foster, MD, Ph.D., is studying how heat and sex hormones regulate inflammation in cells, and simultaneously conducting a clinical trial using hyperthermia (elevating body temperature) in women and men with depression. The goal is to identify targets for temperature control of inflammation that may lead to better treatments for depression and other neuroinflammatory disorders in both sexes.