Amal Kaddoumi, PhD

My research focus is on translational and experimental therapeutics, which includes drug development, the identification of novel therapeutic targets, and translational research aimed at discovering therapies for neurodegenerative diseases, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). My research aims to improve our understanding of how vascular factors contribute to AD and CAA, enabling us to reduce risk and develop treatments that specifically target brain vasculature function.

My research focuses on investigating the following:

• the role of the functional blood-brain barrier (BBB) in maintaining brain function and homeostasis
• role of the vasculature in clearing brain waste products like amyloid-β
• the neurovascular unit that works in concert to maintain a healthy brain
• targeting the BBB as a preventive and therapeutic approach for AD and CAA
• discovery and development of drugs that target brain vasculature dysfunction in AD and CAA
• drugs repurposing for AD and CAA

Current ongoing research projects in my laboratory include:

• Role of blood-brain barrier (BBB) in the pathogenesis of AD and CAA: 
  The blood-brain barrier (BBB) plays a vital role in maintaining the neurovascular unit function and, thus, brain hemostasis. Amyloid-beta (Aβ) accumulation on brain microvessels contributes to the pathogenesis and progression of Aβ vascular pathology related to AD and CAA. Findings from our studies in transgenic mouse models of AD and CAA demonstrated increased BBB leakage and decreased expression of tight junction and transport proteins causing Aβ accumulation, neuroinflammation, and neurodegeneration. My lab produced several publications that support targeting the endothelial cells of the BBB as a preventive and therapeutic approach for AD and related disorders. Based on our findings in this area, my lab is leading multiple research projects to 1) identify therapeutic molecules that target the BBB to enhance its integrity and function, 2) studies on elucidating mechanisms of BBB breakdown, and 3) translational research to test the therapeutic targeting of the BBB as a promising approach to prevent conversion of MCI to AD.
• Drug discovery and development for AD and related disorders:
  Recently, my research team developed an in vitro BBB model with CAA characteristics to high throughput screen (HTS) thousands of compounds to identify hits that could rectify the impaired cell-based BBB model function and integrity. Among the identified hits, several FDA-approved drugs were recognized, a finding which is significant for their potential repurposing to prevent or treat BBB breakdown caused by Aβ in CAA and AD. Repurposing of FDA-approved drugs for treating AD is an innovative approach because these drugs are well-studied and evaluated and could be taken forward to clinical trials, which is one of our primary goals to accomplish in the near future.
• Investigate mechanisms and contributing factors to AD pathology: 
  We found a link between BBB disruption, neurotoxicity, gangliosides dyshomeostasis, and amyloid production. As the pathology of AD is complex, we demonstrated the importance of combination therapy to tackle multiple targets simultaneously.
• Extra-virgin olive oil (EVOO) as a medical food:
  EVOO is one of the main elements of the Mediterranean diet. Several studies have suggested that EVOO has several health-promoting effects that could protect from and decrease the risk of AD; however, the mechanism(s) by which EVOO exerts such effect was unknown. Studies from my lab investigated the effect of EVOO consumption on BBB function and Aβ clearance across the BBB. Our findings demonstrated that adding EVOO, and its bioactive component oleocanthal, to mice diet restored the BBB function and reduced amyloid- and tau-related pathologies. This effect was associated with improved cognitive function. To translate preclinical findings to humans, my lab has conducted a pilot clinical trial to test the hypothesis that “EVOO consumption stops or delays mild cognitive impairment (MCI) conversion to AD by restoring the BBB function in humans” (NCT03824197). Findings demonstrated EVOO to improve the BBB function and improve memory in MCI. Based on these results, my laboratory has currently initiated a second clinical trial utilizing a multi-OMICS approach using transcriptomics, lipidomics, and metabolomics to investigate the biomolecular mechanisms underlying the response of healthy individuals with AD family history to EVOO (NCT05929924).
• Understanding the role of transporters in AD and related disorders pathology:
  Investigate the role of membrane transport proteins in determining drugs and endogenous molecules disposition and their role in neurological diseases, mainly AD and CAA. Investigating and understanding transport proteins is fundamental to facilitate therapeutic development. Transport proteins are widely acknowledged as important determinants governing absorption, clearance, and, in many cases, extent of entry into target organs. There is also a greater appreciation that altered transporter function, whether due to aging, genetic polymorphisms, drug interactions, or environmental factors such as dietary constituents, can result in unexpected adverse effects. Findings from my laboratory demonstrated the vital role of Aβ efflux transport proteins at the BBB in maintaining Aβ brain levels. Thus, understanding transporters’ role in regulating Aβ brain levels is essential not only for understanding the basis for Aβ fluxes from the brain but also could potentially serve as a basis for developing novel therapeutics that target the BBB function and integrity.
• Pharmacokinetic modeling and drug transport/metabolism for drug discovery and development: We also perform in silico prediction of drug pharmacokinetics in humans from in vivo preclinical and in vitro data to optimize drug candidates and dose regimens for further development. The prediction of oral pharmacokinetic behavior prior to initiation of clinical studies would substantially reduce the time and research investment involved in the design of first-in-human clinical studies and would ultimately contribute to the development of safer drugs. This prediction is based on the incorporation of drug permeability and metabolism data and enterocytic blood flow together with zonal and cellular heterogeneous distribution of metabolic enzymes and efflux/uptake transporters in the intestine and liver.

 Complete list of publications