Tag Archives: glaucoma

Non-viral ocular gene therapy with gold nanoparticles and femtosecond lasers

I love the stylistic choice the writer made (pay special attention to the second paragraph) when producing this November 19, 2018 Polytechnique Montréal news release (also on EurekAlert),

A scientific breakthrough by Professor Michel Meunier of Polytechnique Montréal and his collaborators offers hope for people with glaucoma, retinitis or macular degeneration.

In January 2009, the life of engineer Michel Meunier, a professor at Polytechnique Montréal, changed dramatically. Like others, he had observed that the extremely short pulse of a femtosecond laser (0.000000000000001 second) could make nanometre-sized holes appear in silicon when it was covered by gold nanoparticles. But this researcher, recognized internationally for his skills in laser and nanotechnology, decided to go a step further with what was then just a laboratory curiosity. He wondered if it was possible to go from silicon to living matter, from inorganic to organic. Could the gold nanoparticles and the femtosecond laser, this “light scalpel,” reproduce the same phenomenon with living cells?

A very pretty image illustrating the work,

Caption: Gold nanoparticles, which act like “nanolenses,” concentrate the energy produced by the extremely short pulse of a femtosecond laser to create a nanoscale incision on the surface of the eye’s retina cells. This technology, which preserves cell integrity, can be used to effectively inject drugs or genes into specific areas of the eye, offering new hope to people with glaucoma, retinitis or macular degeneration. Credit and Copyright: Polytechnique Montréal

The news release goes on to describe the technology in more detail,

Professor Meunier started working on cells in vitro in his Polytechnique laboratory. The challenge was to make a nanometric incision in the cells’ extracellular membrane without damaging it. Using gold nanoparticles that acted as “nanolenses,” Professor Meunier realized that it was possible to concentrate the light energy coming from the laser at a wavelength of 800 nanometres. Since there is very little energy absorption by the cells at this wavelength, their integrity is preserved. Mission accomplished!

Based on this finding, Professor Meunier decided to work on cells in vivo, cells that are part of a complex living cell structure, such as the eye for example.

The eye and the light scalpel

In April 2012, Professor Meunier met Przemyslaw Sapieha, an internationally renowned eye specialist, particularly recognized for his work on the retina. “Mike”, as he goes by, is a professor in the Department of Ophthalmology at Université de Montréal and a researcher at Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Est-de-l’Île-de-Montréal. He immediately saw the potential of this new technology and everything that could be done in the eye if you could block the ripple effect that occurs following a trigger that leads to glaucoma or macular degeneration, for example, by injecting drugs, proteins or even genes.

Using a femtosecond laser to treat the eye–a highly specialized and fragile organ–is very complex, however. The eye is part of the central nervous system, and therefore many of the cells or families of cells that compose it are neurons. And when a neuron dies, it does not regenerate like other cells do. Mike Sapieha’s first task was therefore to ensure that a femtosecond laser could be used on one or several neurons without affecting them. This is what is referred to as “proof of concept.”

Proof of concept

Mike and Michel called on biochemistry researcher Ariel Wilson, an expert in eye structures and vision mechanisms, as well as Professor Santiago Costantino and his team from the Department of Ophthalmology at Université de Montréal and the CIUSSS de l’Est-de-l’Île-de-Montréal for their expertise in biophotonics. The team first decided to work on healthy cells, because they are better understood than sick cells. They injected gold nanoparticles combined with antibodies to target specific neuronal cells in the eye, and then waited for the nanoparticles to settle around the various neurons or families of neurons, such as the retina. Following the bright flash generated by the femtosecond laser, the expected phenomenon occurred: small holes appeared in the cells of the eye’s retina, making it possible to effectively inject drugs or genes in specific areas of the eye. It was another victory for Michel Meunier and his collaborators, with these conclusive results now opening the path to new treatments.

The key feature of the technology developed by the researchers from Polytechnique and CIUSSS de l’Est-de-l’Île-de-Montréal is its extreme precision. With the use of functionalized gold nanoparticles, the light scalpel makes it possible to precisely locate the family of cells where the doctor will have to intervene.

Having successfully demonstrated proof of concept, Professor Meunier and his team filed a patent application in the United States. This tremendous work was also the subject of a paper reviewed by an impressive reading committee and published in the renowned journal Nano Letters in October 2018.

While there is still a lot of research to be done–at least 10 years’ worth, first on animals and then on humans–this technology could make all the difference in an aging population suffering from eye deterioration for which there are still no effective long-term treatments. It also has the advantage of avoiding the use of viruses commonly employed in gene therapy. These researchers are looking at applications of this technology in all eye diseases, but more particularly in glaucoma, retinitis and macular degeneration.

This light scalpel is unprecedented.

Here’s a link to and a citation for the paper,

In Vivo Laser-Mediated Retinal Ganglion Cell Optoporation Using KV1.1 Conjugated Gold Nanoparticles by Ariel M. Wilson, Javier Mazzaferri, Éric Bergeron, Sergiy Patskovsky, Paule Marcoux-Valiquette, Santiago Costantino, Przemyslaw Sapieha, Michel Meunier. Nano Lett.201818116981-6988 DOI: https://doi.org/10.1021/acs.nanolett.8b02896 Publication Date: October 4, 2018  Copyright © 2018 American Chemical Society

This paper is behind a paywall.

Eye implants inspired by glasswing butterflies

Glasswinged butterfly. Greta oto. Credit: David Tiller/CC BY-SA 3.0

My jaw dropped on seeing this image and I still have trouble believing it’s real. (You can find more image of glasswinged butterflies here in an Cot. 25, 2014 posting on thearkinspace. com and there’s a video further down in the post.)

As for the research, an April 30, 2018 news item on phys.org announces work that could improve eye implants,

Inspired by tiny nanostructures on transparent butterfly wings, engineers at Caltech have developed a synthetic analogue for eye implants that makes them more effective and longer-lasting. A paper about the research was published in Nature Nanotechnology.

An April 30, 2018 California Institute of Technology (CalTech) news release (also on EurekAlert) by Robert Perkins, which originated the news item, goes into more detail,

Sections of the wings of a longtail glasswing butterfly are almost perfectly transparent. Three years ago, Caltech postdoctoral researcher Radwanul Hasan Siddique–at the time working on a dissertation involving a glasswing species at Karlsruhe Institute of Technology in Germany–discovered the reason why: the see-through sections of the wings are coated in tiny pillars, each about 100 nanometers in diameter and spaced about 150 nanometers apart. The size of these pillars–50 to 100 times smaller than the width of a human hair–gives them unusual optical properties. The pillars redirect the light that strikes the wings so that the rays pass through regardless of the original angle at which they hit the wings. As a result, there is almost no reflection of the light from the wing’s surface.

In effect, the pillars make the wings clearer than if they were made of just plain glass.

That redirection property, known as angle-independent antireflection, attracted the attention of Caltech’s Hyuck Choo. For the last few years Choo has been developing an eye implant that would improve the monitoring of intra-eye pressure in glaucoma patients. Glaucoma is the second leading cause of blindness worldwide. Though the exact mechanism by which the disease damages eyesight is still under study, the leading theory suggests that sudden spikes in the pressure inside the eye damages the optic nerve. Medication can reduce the increased eye pressure and prevent damage, but ideally it must be taken at the first signs of a spike in eye pressure.

“Right now, eye pressure is typically measured just a couple times a year in a doctor’s office. Glaucoma patients need a way to measure their eye pressure easily and regularly,” says Choo, assistant professor of electrical engineering in the Division of Engineering and Applied Science and a Heritage Medical Research Institute Investigator.

Choo has developed an eye implant shaped like a tiny drum, the width of a few strands of hair. When inserted into an eye, its surface flexes with increasing eye pressure, narrowing the depth of the cavity inside the drum. That depth can be measured by a handheld reader, giving a direct measurement of how much pressure the implant is under.

One weakness of the implant, however, has been that in order to get an accurate measurement, the optical reader has to be held almost perfectly perpendicular–at an angle of 90 degrees (plus or minus 5 degrees)–with respect to the surface of the implant. At other angles, the reader gives an incorrect measurement.

And that’s where glasswing butterflies come into the picture. Choo reasoned that the angle-independent optical property of the butterflies’ nanopillars could be used to ensure that light would always pass perpendicularly through the implant, making the implant angle-insensitive and providing an accurate reading regardless of how the reader is held.

He enlisted Siddique to work in his lab, and the two, working along with Caltech graduate student Vinayak Narasimhan, figured out a way to stud the eye implant with pillars approximately the same size and shape of those on the butterfly’s wings but made from silicon nitride, an inert compound often used in medical implants. Experimenting with various configurations of the size and placement of the pillars, the researchers were ultimately able to reduce the error in the eye implants’ readings threefold.

“The nanostructures unlock the potential of this implant, making it practical for glaucoma patients to test their own eye pressure every day,” Choo says.

The new surface also lends the implants a long-lasting, nontoxic anti-biofouling property.

In the body, cells tend to latch on to the surface of medical implants and, over time, gum them up. One way to avoid this phenomenon, called biofouling, is to coat medical implants with a chemical that discourages the cells from attaching. The problem is that such coatings eventually wear off.

The nanopillars created by Choo’s team, however, work in a different way. Unlike the butterfly’s nanopillars, the lab-made nanopillars are extremely hydrophilic, meaning that they attract water. Because of this, the implant, once in the eye, is soon encased in a coating of water. Cells slide off instead of gaining a foothold.

“Cells attach to an implant by binding with proteins that are adhered to the implant’s surface. The water, however, prevents those proteins from establishing a strong connection on this surface,” says Narasimhan. Early testing suggests that the nanopillar-equipped implant reduces biofouling tenfold compared to previous designs, thanks to this anti-biofouling property.

Being able to avoid biofouling is useful for any implant regardless of its location in the body. The team plans to explore what other medical implants could benefit from their new nanostructures, which can be inexpensively mass produced.

As if the still image wasn’t enough,

Here’s a link to and a citation for the paper,

Multifunctional biophotonic nanostructures inspired by the longtail glasswing butterfly for medical devices by Vinayak Narasimhan, Radwanul Hasan Siddique, Jeong Oen Lee, Shailabh Kumar, Blaise Ndjamen, Juan Du, Natalie Hong, David Sretavan, & Hyuck Choo. Nature Nanotechnology (2018) doi:10.1038/s41565-018-0111-5 Published: 30 April 2018

This paper is behind a paywall.

ETA May 25, 2018:  I’m obsessed. Here’s one more glasswing image,

Caption: The clear wings make this South-American butterfly hard to see in flight, a succesfull defense mechanism. Credit: Eddy Van 3000 from in Flanders fields – Belgiquistan – United Tribes ov Europe Date: 7 October 2007, 14:35 his file is licensed under the Creative Commons Attribution-Share Alike 2.0 Generic license. [downloaded from https://commons.wikimedia.org/wiki/File:E3000_-_the_wings-become-windows_butterfly._(by-sa).jpg]

Canada’s cannabis biotech and InMed Pharma’s nanoparticle-based drug delivery system grant

Unfortunately, there’s not much detail about the nanoparticle-based drug delivery of what I gather is a form of cannabis useful in the treatment of glaucoma in this April 16, 2015 news item on Azonano,

InMed Pharmaceuticals Inc., a clinical stage biopharmaceutical company that specializes in developing safer, more effective cannabinoid-based therapies, today announced that it has been awarded a grant to further develop the Company’s proprietary nanoparticle-based delivery system for their leading drug candidate CTI-085 for glaucoma.

An April 15, 2015 InMed Pharmaceuticals press release goes on to describe the lead researcher and her past experience, as well as, providing a ‘we’re thrilled and will do wonderful things with this money’ quote,

The Mitacs grant was awarded to Dr. Maryam Kabiri, Ph.D., a researcher with extensive experience in developing nanoparticle-based delivery system. Dr. Kabiri will be working with Prof. Vikramaditya G. Yadav, whose research focuses on metabolic & enzyme engineering and customize novel biosynthetic enzymes that can convert biomass-derived feedstock into better fuels, pharmaceuticals and value-added chemicals. In conjunction with InMed, the Mitacs grant will be utilized to develop a novel delivery system for glaucoma therapy.

Dr. Sazzad Hossain, Chief Scientific Officer, states, “We are pleased to have met the Mitacs funding criteria for the advancement of our proprietary glaucoma delivery system. Not only does this bring us closer to our goals of initiating our Phase 1 trial, but it furthers our business development strategy of having a proprietary delivery system that can be licensed with existing drugs endangered by patent expiration. This “therapy extension” strategy used by drug makers can be a valuable asset to InMed upon successful completion of the program. Additionally, the incorporation of an existing medicine into a new drug delivery system can significantly improve its performance in terms of efficacy, safety, and improved patient compliance.”

About Mitacs
Mitacs is a national, private not-for-profit organization that develops the next generation of innovators with vital scientific and business skills through a suite of unique research and training programs, such as Mitacs-Accelerate, Elevate, Step, Enterprise and Globalink. In partnership with companies, government and universities, Mitacs is supporting a new economy using Canada’s most valuable resource – its people.

For more information on Mitacs, visit www.mitacs.ca.

About InMed
InMed is a clinical stage biopharmaceutical company that specializes in developing cannabis based therapies through the Research and Development into the extensive pharmacology of cannabinoids coupled with innovative drug delivery systems. InMeds’ proprietary platform technology, product pipeline and accelerated development pathway are the fundamental value drivers of the Company.

As is becoming increasingly common, there’s a major focus on business even from Dr. Sazzad Hossain, the company’s chief scientific officer who might be expected to comment on the science. Business used to be the purview of the chief executive officer, the chief financial officer, the chief operating officer,  and/or the chief marketing officer.

I did manage to dig up a bit of information about InMed which was called Cannabis Technologies until fairly recently. Daniel Cossins in a Dec. 1, 2014 article for The Scientist describes the current ‘cannabis pharmaceutical’ scene. The dominant  player on the scene is a UK-based company, GW but InMed merits a mention,

Leading scientists were consulted, including  biotech entrepreneur Geoffrey Guy, who had  previously shown interest in developing cannabis-based medicines. The government granted Guy’s company, GW Pharmaceuticals, a license to grow cannabis plants. Guy’s idea was to generate strains rich in particular cannabinoid compounds that act on the nervous system, then test the effects of various cannabinoid combinations on MS and chronic pain. “It was a case of patient experience guiding scientific exploration,” says Stephen Wright, director of research and development at GW.

In 2010, the company announced the UK launch of its first cannabinoid-based product: Sativex, an oral spray for the treatment of MS spasticity, became the world’s first prescription medicine made from cannabis extracts. Sativex is now approved for use by MS patients in 24 countries, including France, Germany, Italy, and Australia. GW has partnered with Bayer and Novartis to market the  product. It has also signed up with the American branch of Japanese pharma company Otsuka to commercialize the drug in the U.S., where it is currently in Phase 3 clinical trials for treating MS spasticity and cancer pain. Earlier this year, GW’s share price surged when the US Food and Drug  Administration (FDA) granted orphan status to its cannabis-derived antiseizure drug Epidiolex, meaning it will be fast-tracked through clinical trials.

The company’s success is blazing a trail. In recent years, a handful of North American companies have set out on a similar path toward producing cannabis-derived pharmaceuticals. At least one company is developing candidates based on synthetic cannabinoids — of which two are already on the market in the U.S. — while several others are extracting chemical cocktails from the plant. They’re all hoping to capitalize on the anticipated growth of the cannabis pharma space by taking advantage of mounting data on the plant’s therapeutic effects.

“Frankly, we looked at GW and saw that the shift toward pharmacological development of marijuana is  already happening,” says Craig Schneider, president and CEO of InMed Pharmaceuticals (formerly Cannabis Technologies), a Vancouver-based biotech focused on pharmaceutical marijuana. “We see the likes of Otsuka, Novartis, and Eli Lilly diving into the space, and we want to be part of that.”

Cossins’ article goes on to discuss cannibinoids providing a tutorial of sorts on the topic. Meanwhile following on the business aspects of this story, Yahoo Finance  hosts a June 25, 2014 article from Accesswire, which provides some insight into the company, which was still being called Cannabis Technologies, and its GW aspirations,

 Cannabinoids are a diverse set of chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. While tetrahydrocannabinol (“THC”) and cannabidiol (“CBD”) are the two most popular cannabinoids, there are at least 85 different cannabinoids isolated from cannabis exhibiting various effects that could prove therapeutic.

GW Pharmaceuticals plc (GWPH), a biopharmaceutical company focused on discovering, developing, and commercializing novel therapeutics from its proprietary cannabinoid platform, has become the cannabinoid industry’s poster child with a ~$1.4 billion market capitalization and promising data from the clinic for the treatment of Dravet syndrome and Lennox-Gastaut syndrome.

In this article, we’ll take a look at another opportunity in the sector that many are calling the “junior GW” [InMed Pharma, formerly Cannabis Technologies], focused on leveraging its proprietary Cannabinoid Drug Design Platform to rapidly develop cannabinoid-based therapies.

Fully Integrated Platform Play

Cannabis Technologies Inc. (CSE:CAN) (CANLF) is a biopharmaceutical drug discovery and development company focused on cannabinoids that has been dubbed by many as the “Junior GW” in the space. By leveraging its proprietary Cannabinoid Drug Design Platform, management aims to identify new bioactive compounds within the marijuana plant that interact with certain genes.

According to Chief Science Officer Sazzad Hossain, the platform provides the bioinformatics tools necessary to isolate and identify chemical compounds in medical marijuana in months instead of years. The company plans to use the platform to isolate compounds targeting a specific disease and then outsource the early-stage research and trials to get to Phase I quickly and inexpensively.

The company’s initial focus is on the $12 billion ocular diseases market, including the $5.7 billion glaucoma market, where its CTI-085 is preparing to undergo Phase I clinical trials shortly after having completing preclinical trials. In addition to these areas, management also expressed interest in larger market places like pain and inflammation, as well as orphan diseases, cancers, and metabolic diseases.

Similar to GW Pharmaceuticals, the company also operates a breeding and cultivation division that’s responsible for creating its medicines in-house. The proprietary phyto-stock produced by the division sets the firm apart from some of its competitors that rely on third-parties to manufacture their treatments, since the fully-integrated operations are often both lower cost and greater quality.

They certainly have high business hopes for InMed Pharma. As for the science, the company has a Cannabinoid Science webpage on its site,

The majority of pharmaceutical and academic research & development being performed with cannabis revolves around the understanding of its active ingredients, the Cannabinoids

Currently there are between 80-100 cannabinoids that have been isolated from cannabis, that affect the body’s cannabinoid receptors and are responsible for unique pharmacological effects.

There are three general types of cannabinoids: herbal cannabinoids which occur uniquely in the cannabis; endogenous cannabinoids produced in the bodies of humans and animals and synthetic cannabinoids produced in the laboratory.

I was not able to find anything about the company’s nanoparticle-based delivery system on its website.

Nanodiamond contact lenses in attempt to improve glaucoma treatment

A School of Dentistry, at the University of California at Los Angeles (UCLA) or elsewhere, is not my first thought as a likely source for work on improving glaucoma treatment—it turns out that I’m a bit shortsighted (pun intended).  A Feb. 14, 2014 news item on Azonano describes the issue with glaucoma treatment and a new delivery system for it developed by a research team at UCLA,

By 2020, nearly 80 million people are expected to have glaucoma, a disorder of the eye that, if left untreated, can damage the optic nerve and eventually lead to blindness.

The disease often causes pressure in the eye due to a buildup of fluid and a breakdown of the tissue that is responsible for regulating fluid drainage. Doctors commonly treat glaucoma using eye drops that can help the eye drain or decrease fluid production.

Unfortunately, patients frequently have a hard time sticking to the dosing schedules prescribed by their doctors, and the medication — when administered through drops — can cause side effects in the eye and other parts of the body.

In what could be a significant step toward improving the management of glaucoma, researchers from the UCLA School of Dentistry have created a drug delivery system that may have less severe side effects than traditional glaucoma medication and improve patients’ ability to comply with their prescribed treatments. The scientists bound together glaucoma-fighting drugs with nanodiamonds and embedded them onto contact lenses. The drugs are released into the eye when they interact with the patient’s tears.

The new technology showed great promise for sustained glaucoma treatment and, as a side benefit, the nanodiamond-drug compound even improved the contact lenses’ durability.

The Feb. 13, 2014 UCLA news release by Brianna Deane, which originated the news item, describes the nanodiamonds and how they were employed in this project,

Nanodiamonds, which are byproducts of conventional mining and refining processes, are approximately five nanometers in diameter and are shaped like tiny soccer balls. They can be used to bind a wide spectrum of drug compounds and enable drugs to be released into the body over a long period of time.

To deliver a steady release of medication into the eye, the UCLA researchers combined nanodiamonds with timolol maleate, which is commonly used in eye drops to manage glaucoma. When applied to the nanodiamond-embedded lenses, timolol is released when it comes into contact with lysozyme, an enzyme that is abundant in tears.

“Delivering timolol through exposure to tears may prevent premature drug release when the contact lenses are in storage and may serve as a smarter route toward drug delivery from a contact lens.” said Kangyi Zhang, co-first author of the study and a graduate student in Ho’s lab.

One of the drawbacks of traditional timolol maleate drops is that as little as 5 percent of the drug actually reaches the intended site. Another disadvantage is burst release, where a majority of the drug is delivered too quickly, which can cause significant amounts of the drug to “leak” or spill out of the eye and, in the most serious cases, can cause complications such as an irregular heartbeat. Drops also can be uncomfortable to administer, which leads many patients to stop using their medication.

But the contact lenses developed by the UCLA team successfully avoided the burst release effect. The activity of the released timolol was verified by a primary human-cell study.

“In addition to nanodiamonds’ promise as triggered drug-delivery agents for eye diseases, they can also make the contact lenses more durable during the course of insertion, use and removal, and more comfortable to wear,” said Ho, who is also a professor of bioengineering and a member of the Jonsson Comprehensive Cancer Center and the California NanoSystems Institute.

Even with the nanodiamonds embedded, the lenses still possessed favorable levels of optical clarity. And, although mechanical testing verified that they were stronger than normal lenses, there were no apparent changes to water content, meaning that the contact lenses’ comfort and permeability to oxygen would likely be preserved.

By this time, I was madly curious as to what these contact lenses might look like and so I found this image, accompanying the researchers’ paper,  showing what looks like a standard contact lens with an illustration of how the artist imagines the diamonds and medications are functioning at the nanoscale,

nanodiamonds

[downloaded from http://pubs.acs.org/doi/abs/10.1021/nn5002968]

Here’s a link to and a citation for the paper,

Diamond Nanogel-Embedded Contact Lenses Mediate Lysozyme-Dependent Therapeutic Release by Ho-Joong Kim, Kangyi Zhang, Laura Moore, and Dean Ho. ACS Nano, Article ASAP DOI: 10.1021/nn5002968 Publication Date (Web): February 8, 2014

Copyright © 2014 American Chemical Society

This paper is behind a paywall.