What is Drug Therapy?
Dr. Lewis' vision to identify a therapeutic treatment for SIOD within the next two years will require two important steps.
Publishing Novel Results
We must reduce SIOD's complex disease process to the point where researchers can use the CRISPR-edited cell lines to screen potential therapies. In the next year, once the preliminary findings from the cell models are robust and reproducible, Dr. Lewis aims to publish his lab's key findings.
This is a necessary and critical step in order for the team to apply for additional grants to supplement your incredible philanthropy and accelerate progress toward a therapy for SIOD.
Screening Potential Therapies
With grant support from institutions like the National Institutes of Health (NIH), the Lewis Lab will begin screening potential drug candidates for SIOD. To provide clinical benefits on a quicker timeline, the lab will start by screening existing compounds that have already been safely used in human clinical trials or that are FDA-approved, a process that Dr. Lewis estimates will take up to a year.
If an existing drug is not identified as an effective treatment for SIOD, the lab will join forces with academic and industry partners to pursue novel drug therapies.
Phase 1
$318,000
FULLY FUNDED 2022
Background: We now have genetically engineered induced pluripotent stem cells (IPSCs) that can be treated to specifically deplete SMARCAL1 protein using a drug. This will model SIOD, in which all cells of body have impaired production of SMARCAL1 due to genetic.
We can now make tissues/organoids from these IPSCs that are affected with disease in SIOD – this includes “Brain on a Chip” that includes brain tissue and blood vessels that provide nutrients to the brain.
Hypothesis: SMARCAL1 is important for the blood vessel cells dealing with many causes of stress, such as increased temperature. Depletion SMARCAL1 of the tissue/organoids will lead to changes in the cells signaling and temporary narrowing of the brain blood vessels. In SIOD, this is likely what results in migraine like headaches and temporary neurologic dysfunction.
Proposal: Modeling of Neurovascular Disease in SIOD Objective: Use the brain-on-a-chip system maintained underphysiologic conditions to study effects of the lack of SMARCAL1 protein on blood vessel cell function in a brain organoid. To gain insight as to how SMARCAL1 protein causes disease, such as migraine headaches with neurologic dysfunction, this will be constructed using blood vessel cells that can be treated with a drug to induce SMARCAL 1 deficiency.
Phase 2
FULLY FUNDED 2024
$347,500
Background: Assuming that Phase 1 is successful in identifying abnormalities in cell signaling, gene expression, or biologic function, the next step will be to perform drug screens to determine if treatment with small molecules can partially or fully correct the pathologic features.
Hypothesis: We expect that the phase 1 studies using neurovascular chips will reveal abnormalities with drug-induced SMARCAL1 depletion that are shared with other diseased tissues, e.g., kidney and blood vessel organoids. We predict that treatment with small molecules as part of drug screens will identify several candidates for further preclinical drug development, which will be pursued in phase 3.
Proposal: Small and Large Scale Drug Screens for Neurovascular Disease. Objective: Perform Screens of repurposed small molecule drugs and a large scale small molecule screen to identify drugs that can correct the biologic abnormalities in the neurovascular model of SIOD. Validate any positive hits in each screen using the Brain on a Chip System.