Faculty

Jacob S Brenner, MD, PhD

faculty photo
Assistant Professor of Medicine (Pulmonary, Allergy and Critical Care)
Department: Medicine
Graduate Group Affiliations

Contact information
3450 Hamilton Walk
Stemmler Building, Office #220
Philadelphia, PA 19104
Office: 215-662-2222
Education:
BA (Molecular Biology)
Princeton University, 2001.
PhD (Chemical & Systems Biology / Molecular Pharmacology)
Stanford University, 2007.
MD (Medical Scientist Training Program)
Stanford University, 2010.
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Description of Clinical Expertise

Dr. Brenner attends in the Medical Intensive Care Unit (MICU) at the Hospital of the University of Pennsylvania. He is board certified and fellowship trained in critical care.

Description of Other Expertise

Dr. Brenner teaches medical entrepreneurship at Penn, as part of Penn Health-Tech (Penn's medical device center). Dr. Brenner previously started 3 funded medical device companies, one of which has already achieved FDA approval for a first-in-class device.

Description of Research Expertise

Dr. Brenner’s lab (www.brennerbioengineeringlab.com) engineers new technologies for the diseases of Pulmonary & Critical Care Medicine (PCCM). PCCM encompasses both diseases of the lungs and acute critical illnesses (ACIs), which means all acutely life-threatening diseases, such as ARDS, stroke, sepsis, & more.

Dr. Brenner’s lab engineers technologies ranging from the macro-scale (devices you can hold), all the way down to the nano-scale (smaller than cells). On the macro-scale, Dr. Brenner has spun out 3 funded medical device companies, including one with FDA approval, and his most recent one, RightAir (www.rightair.io/), is currently in clinical studies with its AIR-AD Vest to relieve shortness of breath in COPD patients.

The nano-scale is where Dr. Brenner’s lab spends most of their time, developing nanomedicine for acute critical illnesses (ACIs). ACIs are a huge class of diseases, accounting for costs that are 4% of the US GDP! Unfortunately, there are few if any disease-specific drugs, and the outcomes remain very poor.

In developing new approach for ACIs, it is notable that they all share 3 unique pharmacological challenges: 1) ACI patients are fragile, with multiple simultaneous organ systems perturbed, so they do not tolerate the off-target side effects of drugs (side effects in remote organs). 2) ACIs are heterogeneous, with multiple subgroups and cell types implicated, so therapy targeting a single pathway is unlikely to work. 3) These diseases are rapidly progressive, so each signaling pathway is active for only a short time window.

To solve these 3 pharmacological challenges and thereby create a platform technology for treating ACIs, the Brenner Lab has been developing VMNs (vascular-targeted, multi-drug-loaded nanocarriers). VMNs are ~100-nanometer drug carriers that when injected intravascularly concentrate strongly in the target organ, using a variety of targeting mechanisms explained below. By concentrating drugs in the diseased organ, VMNs eliminate the off-target side effects of cargo drugs, solving problem #1 above. By shuttling multiple drugs, they address multiple points of pathology, solving the heterogeneity problem (#2 above) and the issue that ACIs are rapidly progressive (#3). The lab chose vascular-targeting for VMNs because nearly all ACIs are vascular-oriented, with pathology largely residing in the blood vessels, in the form of inflammation, thrombosis, and ischemia. Additionally, intravascular access for infusing VMNs is easy in ACI patients, as they all have IVs, and it is common to put in intra-arterial (IA) catheters during procedures (e.g., for stroke and heart attack).

Dr. Brenner and his lab have created a number of targeting mechanisms for VMNs so that they can target any organ affected by ACIs, and address the VMNs to particular cell types. The first such technology, developed in the 1990s by Dr. Brenner’s former postdoc advisor and continued close collaborator, Dr. Vlad Muzykantov, involves conjugating to VMNs’ surface affinity moieties (e.g., antibodies and derivatives thereof) that bind to endothelial cells (see Dr. Brenner’s publications with PMIDs 28065731, 28304180). The second such technology Dr. Brenner co-developed is RBC-hitchhiking (RH), in which VMNs are adsorbed onto red blood cells, which facilitates transfer to the capillary endothelium, without needing antibodies (PMID 29992966). Combined with IA catheters, RH achieved the highest published levels of delivery to organs such as the kidney (for the ACI acute kidney injury) and brain (for treating stroke, where RH achieved >10x the brain delivery of the best prior technology). Finally, more recently, in unpublished work, the Brenner lab has developed a technology for targeting VMNs to resident leukocytes in organs affected by ACIs.

With this suite of targeting mechanisms, the Brenner lab is now identifying the optimal combinations of drugs to load into VMLs. The lab is interested in using computational techniques to predict the best drugs to load (PBPK modeling, network pharmacology), and then testing the drugs in multiple animal models of disease. The Brenner lab primarily uses rodent models, but in order to maximize translational potential, also employs large animal models (pigs) and even fresh, ex vivo human organs that have been rejected for transplant, usually because they are afflicted by the ACIs that are the lab’s focus (PMID 29992966). The goal is to develop VMNs for each ACI, and move them to patients by partnering with industry, which the Brenner lab already has done by forming a close collaboration with a pharmaceutical company in developing VMNs for ARDS.

Please join the Brenner lab in the fight, building technologies to defeat these terrible diseases!

Selected Publications

Lee HS, Kim YC, Wang Z, Brenner JS, Muzykantov VR, Myerson JW, Composto RJ.: Controlling spatial distribution of functional lipids in a supported lipid bilayer prepared from vesicles. J Colloid Interface Sci 664: 1042-1055, Jun 2024.

Nong J, Glassman PM, Shuvaev VV, Reyes-Esteves S, Descamps HC, Kiseleva RY, Papp TE, Alameh MG, Tam YK, Mui BL, Omo-Lamai S, Zamora ME, Shuvaeva T, Arguiri E, Gong X, Brysgel TV, Tan AW, Woolfork AG, Weljie A, Thaiss CA, Myerson JW, Weissman D, Kasner SE, Parhiz H, Muzykantov VR, Brenner JS, Marcos-Contreras OA.: Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke. Mol Ther 32: 1344-1358, May 2024.

Zamora ME, Omo-Lamai S, Patel MN, Wu J, Arguiri E, Muzykantov VR, Myerson JW, Marcos-Contreras OA, Brenner JS.: Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting. Nano Lett Apr 2024.

Greenwood JC, Talebi FM, Jang DH, Spelde AE, Gordon EK, Horak J, Acker MA, Kilbaugh TJ, Shofer FS, Augoustides JGT, Brenner JS, Muzykantov VR, Bakker J, Abella BS.: Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass. Crit Care Med Apr 2024.

Ebrahimimojarad A, Wang Z, Zhang Q, Shah A, Brenner JS, Fu J.: A Robust and Efficient Method to Purify DNA-Scaffolded Nanostructures by Gravity-Driven Size Exclusion Chromatography. Langmuir 40: 8365-8372, Apr 2024.

Omo-Lamai S, Zamora ME, Patel MN, Wu J, Nong J, Wang Z, Peshkova A, Majumder A, Melamed JR, Chase LS, Essien EO, Weissman D, Muzykantov VR, Marcos-Contreras OA, Myerson JW, Brenner JS.: Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions. Adv Mater e2312026, Feb 2024 Notes: doi: 10.1002/adma.202312026. Online ahead of print.

Marcos-Contreras OA, Myerson JW, Nong J, Brenner JS, Muzykantov VR, Glassman PM.: Effective Prevention of Arterial Thrombosis with Albumin-Thrombin Inhibitor Conjugates. Mol Pharm 20: 5476-5485, Nov 2023.

Chase LS, Zaleski MH, Morrell LJ, Brenner JS.: Automated measurement of distance-walked as a "sixth vital sign" for detecting infusion reactions during preclinical testing. Int J Pharm 645: 123369, Oct 2023.

Nong J, Glassman PM, Myerson JW, Zuluaga-Ramirez V, Rodriguez-Garcia A, Mukalel A, Omo-Lamai S, Walsh LR, Zamora ME, Gong X, Wang Z, Bhamidipati K, Kiseleva RY, Villa CH, Greineder CF, Kasner SE, Weissman D, Mitchell MJ, Muro S, Persidsky Y, Brenner JS, Muzykantov VR, Marcos-Contreras OA.: Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain. ACS Nano 17: 13121-13136, Jul 2023.

Macedo B, Patel M, Zaleski MH, Mody P, Ma X, Mei P, Myerson JW, Brenner JS, Glassman PM.: Meta-analysis of material properties influencing nanoparticle plasma pharmacokinetics. Int J Pharm 639: 122951, May 2023.

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Last updated: 05/13/2024
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