Joseph Arboleda-Velasquez

Dr. Arboleda-Velasquez’s research is focused on the genetics and pathobiology of neurodegenerative diseases of the brain and the retina. He began his career studying brain and retinal small-vessel disease (SVD) during his PhD training at Harvard Medical School and postdoctoral fellowship at Mass Eye and Ear, and recently expanded his research to include mechanisms of resistance to Alzheimer’s disease. Dr. Arboleda-Velasquez’s most significant achievements to date include:

Showed that Notch signaling, a key regulator of cell fate decisions, plays a central role in the pathophysiology of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; the most common inherited SVD of the brain) and, more generally, in ischemic stroke. Showed that pericytes (multifunctional, fibroblast-like cells found in the walls of CNS capillaries) help maintain retinal microvasculature stability in adults, a finding relevant to a retinal SVD called diabetic retinal microangiopathy. Discovered a role for the transcription factor Runx1 in aberrant angiogenesis and fibrosis. Developed an approach for discovering rare gene variants of large effect contributing to the resistance to neurodegeneration in Alzheimer’s disease – an approach that uncovered the APOE3 Christchurch variant. The APOE3 Christchurch article published in Nature Medicine in November of last year already has 76 citations and has been ranked in the top 5% of all time research outputs scored by Altmetric. Dr. Arboleda-Velasquez’s early career work on CADASIL, an inherited form of stroke and vascular dementia, took him from the clinical characterization of two families in his home country of Colombia to Harvard Medical School, where he conducted molecular studies of mutant Notch 3 receptors in culture systems. He also generated novel knock-in mouse models that replicated a genotype-phenotype correlation first observed in his CADASIL patients, and leveraged inducible cell ablation studies in mice to provide evidence that pericytes help regulate microvascular stability in adult neural tissues. Dr. Arboleda-Velasquez recently took his CADASIL work towards translational applications by characterizing blood biomarkers linked to the pathobiology of the disease and by establishing the preclinical feasibility of a treatment modality based on Notch 3 signaling normalization using therapeutic antibodies.

Dr. Arboleda-Velasquez’s current research program also encompasses vitreoretinal diseases, with focuses on two relatively uncharted conditions: diabetic retinopathy, the most common cause of permanent blindness in working adults in the US, and proliferative vitreoretinopathy, a severe complication of ocular trauma. To drive innovation towards the discovery of new therapeutic targets, he developed new methods for the primary culture and molecular profiling of human cells derived from surgical specimens from patients with these conditions. These efforts led to: 1) the discovery of Runx1 as a critical mediator of aberrant angiogenesis in proliferative diabetic retinopathy and in the epithelial-to-mesenchymal transition in proliferative vitreoretinopathy; 2) the development of new treatment modalities based on administering small molecule inhibitors of Runx1 as eye drop formulations; and 3) the development of new animal models for proliferative vitreoretinopathy that reproduce the complexity of the human condition.

More recently, he initiated a research program addressing genetic factors underlying resistance to Alzheimer’s disease by leveraging his access to the world’s largest population of patients with familial Alzheimer’s disease caused by the E280A mutation in Presenilin 1 (PSEN1 E280A). Dr. Arboleda-Velasquez is leading a collaborative project to conduct deep phenotyping and genomic and proteomic analyses of subjects with unusually late ages of symptom onset, with the goal of identifying and validating new rare gene variants of large effect capable of conferring resistance to neurodegeneration.

Education

• MD, University of Antioquia, Medellin Colombia (2000)
• PhD, Harvard Medical School (2009)

Postgraduate Training

• Research Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear (2010-2011)

Honors

• 2015: Young Mentor Award, Harvard Medical School
• 2015: Leadership Development for Physicians and Scientists Program, Harvard Medical School
• 2015: Early Career Institute in Neuroscience Travel and Mentoring Minority Award, NINDS-University of Pittsburg
• 2012: Carl Storm Underrepresented Minority Fellowship, Gordon Research Conference
• 2011: Society of Neuroscience Scholar Fellow Award