Jacob S Brenner, MD, PhD

faculty photo
Assistant Professor of Medicine
Department: Medicine
Graduate Group Affiliations

Contact information
3450 Hamilton Walk
Stemmler Building, Office #220
Philadelphia, PA 19104
Office: 215-662-2222
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

Rubey KM , Mukhitov AR, Nong J, Krymskaya VP, Myerson JW, Worthen GS, Brenner JS: Nanoparticle-induced augmentation of neutrophils’ phagocytosis of bacteria. Frontiers in Pharmacology 2022 (accepted 5/31/22).

Xin Y, Cereda M, Yehya N, Humayun S, Delvecchio P, Thompson JM, Martin K, Hamedani H, Martorano P, Duncan I, Kadlecek S, Makvandi M, Brenner JS, Rizi RR.: Imatinib alleviates lung injury and prolongs survival in ventilated rats. Am J Physiol Lung Cell Mol Physiol 322: L866-L872, Jun 2022.

Ferguson LT, Hood ED, Shuvaeva T, Shuvaev VV, Basil MC, Wang Z, Nong J, Ma X, Wu J, Myerson JW, Marcos-Contreras OA, Katzen J, Carl JM, Morrisey EE, Cantu E, Villa CH, Mitragotri S, Muzykantov VR, Brenner JS.: Dual Affinity to RBCs and Target Cells (DART) Enhances Both Organ- and Cell Type-Targeting of Intravascular Nanocarriers. ACS Nano 16: 4666-4683, Mar 2022.

Myerson JW, Patel PN, Rubey KM, Habibi N, Walsh LR, Lee Y-W, Luther DC, Ferguson LT, Zaleski MH, Zamora ME, Marcos-Contreras OA, Glassman PM, Johnston I, Hood ED, Shuvaeva T, JV, Kiseleva RY, Nong J, Greineder CF, Mitragotri S, Worthen GS, Rotello VM, Lahann J, Muzykantov VR, Brenner JS : Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation. Nature Nanotechnology January 2022.

Wang Z, Hood ED, Nong J, Ding J, Marcos-Contreras OA, Glassman PM, Rubey KM, Zaleski M, Espy CL, Gullipali D, Miwa T, Muzykantov VR, Song WC, Myerson JW, Brenner JS.: Combating Complement's Deleterious Effects on Nanomedicine by Conjugating Complement Regulatory Proteins to Nanoparticles. Adv Mater 2022.

Parhiz H, Brenner JS, Patel PN, Papp TE, Shahnawaz H, Li Q, Shi R, Zamora ME, Yadegari A, Marcos-Contreras OA, Natesan A, Pardi N, Shuvaev VV, Kiseleva R, Myerson JW, Uhler T, Riley RS, Han X, Mitchell MJ, Lam K, Heyes J, Weissman D, Muzykantov VR.: Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). J Control Release 2022.

Kanter K, Gallagher R, Eweje F, Lee A, Gordon D, Landy S, Gasior J, Soto-Calderon H, Cronholm PF, Cocchiaro B, Weimer J, Roth A, Lankenau S, Brenner J: Willingness to use a wearable device capable of detecting and reversing overdose among people who use opioids in Philadelphia. Harm Reduct J 18(1): 75, Jul 2021.

Marcos-Contreras OA, Greineder CF, Kiseleva RY, Parhiz H, Walsh LR, Zuluaga-Ramirez V, Myerson JW, Hood ED, Villa CH, Tombacz I, Pardi N, Seliga A, Mui BL, Tam YK, Glassman PM, Shuvaev VV, Nong J, Brenner JS, Khoshnejad M, Madden T, Weissmann D, Persidsky Y, Muzykantov VR.: Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier. Proc Natl Acad Sci U S A. 117(7): 3405-3414, Feb 2020.

Mendes LP, Rostamizadeh K, Gollomp K, Myerson JW, Marcos-Contreras OA, Zamora M, Luther E, Brenner JS, Filipczak N, Li X, Torchilin VP: Monoclonal antibody 2C5 specifically targets neutrophil extracellular traps MAbs 12(1): 1850394, January 2020.

Marcos-Contreras OA, Brenner JS, Kiseleva RY, Zuluaga-Ramirez V, Greineder CF, Villa CH, Hood ED, Myerson JW, Muro S, Persidsky Y, Muzykantov VR: Combining vascular targeting and the local first pass provides 100-fold higher uptake of ICAM-1-targeted vs untargeted nanocarriers in the inflamed brain. J Control Release 301: 54-61, May 2019.

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Last updated: 06/14/2022
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