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!
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 : 54-61,2019.
Paris AJ, Guo L, Dai N, Katzen JB, Patel PN, Worthen GS, Brenner JS: Using selective lung injury to improve murine models of spatially heterogeneous lung diseases PLoS One 14 (4): 2019.
Parhiz H, Shuvaev VV, Pardi N, Khoshnejad M, Kiseleva RY, Brenner JS, Uhler T, Tuyishime S, Mui BL, Tam YK, Madden TD, Hope MJ, Weissman D, Muzykantov VR.: PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake. J Control Release 10 : 106-115,2018.
Muzykantov VR, Brenner JS: Vascular Immunotargeting: Take the Highway to the First Exit. Hepatology 68 (5): 1672-1674,2018.
Brenner JS*, Pan D*, Myerson J*, Marcos-Contreras OA*, et al: RBC-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude Nature Communications 9 (1): 2648,2018.
Parhiz H, Khoshnejad M, Myerson JW, Hood E, Patel PN, Brenner JS, Muzykantov VR.: Unintended effects of drug carriers: Big issues of small particles. Adv Drug Deliv 130 : 90-112,2018.
Pan Daniel C, Myerson Jacob W, Brenner Jacob S, Patel Priyal N, Anselmo Aaron C, Mitragotri Samir, Muzykantov Vladimir: Nanoparticle Properties Modulate Their Attachment and Effect on Carrier Red Blood Cells. Scientific reports 8 (1): 1615,2018.
Brenner Jacob S, Kiseleva Raisa Yu, Glassman Patrick M, Parhiz Hamideh, Greineder Colin F, Hood Elizabeth D, Shuvaev Vladimir V, Muzykantov Vladimir R: The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series). Pulmonary circulation 8 (1): 2045893217752329,2018.
Khoshnejad Makan, Brenner Jacob S, Motley William, Parhiz Hamideh, Greineder Colin F, Villa Carlos H, Marcos-Contreras Oscar A, Tsourkas Andrew, Muzykantov Vladimir R: Molecular engineering of antibodies for site-specific covalent conjugation using CRISPR/Cas9. Scientific reports 8 (1): 1760,2018.
Brenner JS, Bhamidipati K, Glassman P, Ramakrishnan N, Jiang D, Paris AJ, Myerson JW, Pan DC, Shuvaev VV, Villa C, Hood ED, Kiseleva R, Greineder CF, Radhakrishnan R, Muzykantov VR: Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions. Nanomedicine
13 (4): 1495-1506,2017.
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