Science Translational Medicine: Tyrosine kinase blocking collagen IV–derived peptide suppresses ocular neovascularization and vascular leakage

New peptide could improve treatment for vision-threatening disease

http://stm.sciencemag.org/content/9/373/eaai8030
Press Release by Science Daily
Press Release by Johns Hopkins Medicine

A better drug for diseases of the retina

Blood vessel misbehavior causes several retinal diseases, including macular degeneration and diabetic retinopathy. Injections of the current treatment aflibercept can hold these diseases at bay but cannot reverse pathology, and the effects do not last long, dictating frequent injections. Lima e Silva et al. have now come up with something better. Rather than a large antibody-like protein like aflibercept, they have zeroed in on the tiny peptides that naturally prevent blood vessel overgrowth in the body. They find that AXT107, a peptide derived from collagen IV, does the trick. In multiple mouse and rabbit models of retinal disease, this agent works as well as or better than aflibercept—perhaps because it inhibits multiple growth factor pathways, not just VEGF. As a bonus, AXT107 gathers as a gel within the eye, allowing it to inhibit disease for longer periods of time. AXT107 may form the basis of a new generation of drugs to augment current approaches to macular degeneration and diabetic retinopathy.

 

Abstract

Vascular endothelial growth factor (VEGF)–neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c-Met, and PDGFRβ. Optimal signaling through these receptors requires complex formation with β3 integrin, which was reduced by AXT107 binding to αvβ3. AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins.

 

Raquel Lima e Silva1,2,*Yogita Kanan1,2,*Adam C. Mirando3Jayoung Kim3,4Ron B. Shmueli3,4Valeria E. Lorenc1,2Seth D. Fortmann1,2Jason Sciamanna1,2Niranjan B. Pandey3,5Jordan J. Green1,3,4,6Aleksander S. Popel3 and Peter A. Campochiaro1,2,

+ Author Affiliations
↵†Corresponding author. Email: pcampo@jhmi.edu
↵* These authors contributed equally to this work.
Science Translational Medicine 18 Jan 2017:
Vol. 9, Issue 373,
DOI: 10.1126/scitranslmed.aai8030

 

Nano Letters: Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions

Noninvasive Ultrasound Pulses Used to Precisely Tweak Rat Brain Activity

Press Release by Futurity
Press Release by Johns Hopkins Medicine

Abstract


Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

 

† Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
‡ Department of Biomedical Engineering and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
§ Department of Radiology, Stanford University, Stanford, California 94305, United States
∥ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21231, United States
⊥ National Cancer Institute/National Institutes of Health, Bethesda, Maryland 20892, United States
# Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
∇ Neuroscience Laboratory, Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland 21287, United States
○ Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, United States
◆ Departments of Neurosurgery, Ophthalmology, and Materials Science and Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
Nano Lett., Article ASAP
DOI: 10.1021/acs.nanolett.6b03517
Publication Date (Web): January 17, 2017
Copyright © 2017 American Chemical Society

Nano Nugget – The National Nanotechnology Initiative

Nano Nugget featuring Jordan Green

Dr. Green discusses how nanotechnology will impact medicine.

Work funded by @NIH & @NIBIB

Nature: Mimicking biological functionality with polymers for biomedical applications

Jordan J. Green & Jennifer H. Elisseeff

Nature 540, 386–394 (15 December 2016) doi:10.1038/nature21005
Received 06 January 2016 Accepted 12 September 2016 Published online 14 December 2016

Abstract

The vast opportunities for biomaterials design and functionality enabled by mimicking nature continue to stretch the limits of imagination. As both biological understanding and engineering capabilities develop, more sophisticated biomedical materials can be synthesized that have multifaceted chemical, biological and physical characteristics designed to achieve specific therapeutic goals. Mimicry is being used in the design of polymers for biomedical applications that are required locally in tissues, systemically throughout the body, and at the interface with tissues.

http://www.nature.com/nature/journal/v540/n7633/full/nature21005.html

TERMIS Young Investigator Award

William R. Wagner, ‪@ActaBio Editor, presents Jordan Green with ‪@TERMISAM Young Investigator Award. CONGRATULATIONS @JGreenGroup!

Biomaterials: Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma

Abstract

Biomimetic materials that target the immune system and generate an anti-tumor responses hold promise in augmenting cancer immunotherapy. These synthetic materials can be engineered and optimized for their biodegradability, physical parameters such as shape and size, and controlled release of immune-modulators. As these new platforms enter the playing field, it is imperative to understand their interaction with existing immunotherapies since single-targeted approaches have limited efficacy. Here, we investigate the synergy between a PLGA-based artificial antigen presenting cell (aAPC) and a checkpoint blockade molecule, anti-PD1 monoclonal antibody (mAb). The combination of antigen-specific aAPC-based activation and anti-PD-1 mAb checkpoint blockade induced the greatest IFN-γ secretion by CD8+ T cells in vitro. Combination treatment also acted synergistically in an in vivo murine melanoma model to result in delayed tumor growth and extended survival, while either treatment alone had no effect. This was shown mechanistically to be due to decreased PD-1 expression and increased antigen-specific proliferation of CD8+ T cells within the tumor microenvironment and spleen. Thus, biomaterial-based therapy can synergize with other immunotherapies and motivates the translation of biomimetic combinatorial treatments.

A.K. Kosmidesabce1R.A. Meyerade1J.W. HickeyabceK. AjebcK.N. CheungadJ.J. GreenadefghJ.P. Schneckbcei

a Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
b Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
c Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
d Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
e Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
f Department of Materials Science and Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
g Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
h Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
i Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

 

Press Release by Johns Hopkins Medicine

http://www.sciencedirect.com/science/article/pii/S0142961216306639

Advanced Drug Delivery Reviews: Gene delivery nanoparticles to modulate angiogenesis

Abstract

Angiogenesis is naturally balanced by many pro- and anti-angiogenic factors while an imbalance of these factors leads to aberrant angiogenesis, which is closely associated with many diseases. Gene therapy has become a promising strategy for the treatment of such a disordered state through the introduction of exogenous nucleic acids that express or silence the target agents, thereby engineering neovascularization in both directions. Numerous non-viral gene delivery nanoparticles have been investigated towards this goal, but their clinical translation has been hampered by issues associated with safety, delivery efficiency, and therapeutic effect. This review summarizes key factors targeted for therapeutic angiogenesis and anti-angiogenesis gene therapy, non-viral nanoparticle-mediated approaches to gene delivery, and recent gene therapy applications in pre-clinical and clinical trials for ischemia, tissue regeneration, cancer, and wet age-related macular degeneration. Enhanced nanoparticle design strategies are also proposed to further improve the efficacy of gene delivery nanoparticles to modulate angiogenesis.

 

 

http://www.sciencedirect.com/science/article/pii/S0169409X16303167

Jayoung Kimab1Adam C. Mirandoac1Aleksander S. PopelacJordan J. Greenabcd
a Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
b Translational Tissue Engineering Center and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
c Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
d Departments of Ophthalmology, Neurosurgery, and Materials Science & Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Received 18 June 2016, Revised 1 October 2016, Accepted 24 November 2016, Available online 30 November 2016

Dr. Green Honored at the 2016 AIChE Annual Meeting with the AIChE Allan P. Colburn Award



Jordan Green was honored to receive the 2016 Allan P. Colburn Award for Excellence in Publications by a Young Member of the American Institute of Chemical Engineers(AIChE). Dr. Green is an Associate Professor of Biomedical Engineering, Ophthalmology, Oncology, Neurosurgery, and Materials Science & Engineering at the Johns Hopkins University School of Medicine. On being informed of the award Dr. Green commented, “It is such an honor to be in the same company as the other award recipients.”

The award encourages excellence in publications by a younger member of the Institute (<36 years of age) and is presented to one member each year. The Allan P. Colburn Award is one of the Institute’s most prestigious awards, honoring eminent chemical engineers for career accomplishments, service to society, and service to the institute. The award will be presented at the Honors Ceremony of the AIChE Annual Meeting in November. Awardees receive a plaque and cash prize of $5,000.

 

GA Tech Invited Talk and SFB Day

http://petitinstitute.gatech.edu/biomaterials-day

Southeast Biomaterials Day 2016

The Georgia Institute of Technology, with Clemson University, will host the Southeast Biomaterials Day on Friday, October 14, 2016. This all-day research conference organized by Georgia Tech’s Student Chapter of the Society for Biomaterials is designed to build regional biomaterials  networking opportunities by inviting attendees from surrounding schools, industry, and government.

The meeting format will include plenary talks from guest lecturers, faculty talks from invited speakers, student talks, an industry panel discussion, and a student poster session and competition, and will conclude with a networking reception.

REGISTRATION NOW OPEN

Early registration (available through September 21, 2016) – $15, all attendees
Regular registration (beginning September 22, 2016) – $25, all attendees

Abstract Submission Process is Now Open – Deadline August 31 (National SFB submissions deadline September 5)!

Our 2014 Biomaterials day was a huge success with attendees from Georgia Tech and 9 other universities including an especially large showing from our co-hosts for the Southeast Biomaterials Day, Clemson University. This is a great opportunity to share cutting-edge biomaterials research with future collaborators, and our last event sold out early with over 150 scientists and trainees in attendance from academia, government, and industry. We expect this year’s event to be even bigger and better, so register soon!

Plenary Speakers

Jordan Green, Ph.D.
Associate Professor of Biomedical Engineering, Ophthalmology, Oncology, Neurosurgery, and Materials Science & Engineering
Johns Hopkins University

Engineered Biomaterials for Biomimicry: Gene Delivery Nanoparticles and Artificial Antigen Presenting Cells

Elana, Kelly, Hannah Join Our Lab

Welcome to the new BME Ph.D. students who have recently joined the Green Group!

Elana Ben-Akiva (B.S., Biological Engineering from MIT) , Kelly Rhodes (B.S., Bioengineering from the University of Maryland), and Hannah Vaughan (B.S., Biomedical Engineering from Duke University)