Retinitis pigmentosa, a degenerative genetic disease of the eye, is characterized by progressive vision loss, usually leading to blindness. In some patients, structural defects in the photoreceptor cells have been observed, but the molecular mechanisms involved are not understood.

A team from the University of Geneva (UNIGE), in collaboration with the University of Lausanne (UNIL), has identified the essential role played by a molecular zipper formed by four proteins. The absence of this zipper leads to cell death in retinal cells. This discovery could lead to the development of therapeutic approaches for 

. This work can be read in the journal 

According to a news release form the University of Geneva, retinitis pigmentosa

 is the most common hereditary retinal disease in humans, with a prevalence of one in every 4000 people worldwide. The first symptoms usually appear between the ages of 10 and 20 with a loss of night vision. Thereafter, the visual field narrows into a “tunnel vision” to finally lead to blindness around the age of 40. This disease is characterized by a degeneration of the light sensitive cells, the photoreceptors.

The university noted in the release that these specialized neuronal cells of the retina are responsible for the conversion of light into a nerve signal. The outer segment of the cell is made up of stacks of discs on which the light-sensitive pigments are located. The inner segment contains all the metabolic machinery essential to the functioning of the cell and is linked to the outer segment by the connecting cilium.

Mutations in the genes of four proteins located in this connecting cilium are all associated with retinal pathologies presenting degeneration of photoreceptors. These four proteins had been identified by the laboratory of Drs Paul Guichard and Virginie Hamel of the Department of Molecular and Cellular Biology of the Faculty of Science. They are located in centrioles, cylindrical structures made of microtubules and present in all animal cells.

“In the centriole, these proteins ensure the cohesion of the different microtubules by acting like a zipper. We wondered if they did not play the same role in the tubular structures of the connecting cilium”, explained Hamel, last author of the study, said in the release.

Observations with unprecedented precision

Thanks to an expansion microscopy technique optimized by the group of Drs Hamel and Guichard, which allow cells to be inflated without deforming them, the scientists were able to observe retinal tissue with a resolution never achieved. The biologists focused on the structure of connecting cilia from mice that had - or did not have - a mutation in the gene for one of the four mentioned proteins.

These observations were conducted at different life stages.

“In the absence of the mutation, we found that these proteins ensure, just as we had previously seen in centrioles, the cohesion between microtubules by forming a zipper that closes as development proceeds,” Olivier Mercey, researcher in the Department of Molecular and Cellular Biology and first author of the study, said in the release.

On the other hand, when the gene for this protein is mutated, although the structure of the microtubules appears normal in the first days, the microtubules gradually become less and less attached to each other. In adulthood, the affected mice have microtubules that are no longer “zipped” together at all and eventually collapse, leading to cell death of the photoreceptors.

Restoring the “molecular zipper” to prevent cell death

According to the university, this work, supported by the European Research Council (ERC) and the Pro Visu Foundation, has led to a better understanding at the molecular and structural level of 

 which allows to consider therapeutic treatments that act upstream of cell degeneration.

“By injecting the protein into patients suffering from certain types of 

, we can imagine that the molecular zipper could be restored to ensure the structural integrity of the microtubules of the connecting cilia, thus preventing the death of photoreceptor cells,” Dr Guichard concluded. “We are evaluating this approach in collaboration with our colleagues from UNIL and the Jules-Gonin Ophthalmic Hospital, Yvan Arsenijevic and Corinne Kostic.”

1. Olivier Mercey, PhD; Paul Guichard, PhD; et al. The connecting cilium inner scaffold provides a structural foundation that protects against retinal degeneration. 

 published June 16, 2022. doi 10.1371.journal.pbio.3001649

Articles

A team led by researchers from the University of Geneva has identified a molecular mechanism that causes degeneration of the eye’s photoreceptors, which can lead to blindness.

Newly identified molecular mechanism may lead to more therapies for retinitis pigmentosa 

A specific cell within the retina appears to be particularly good at housing Ebola and other viruses, new research has found.

A highly infectious and lethal viral disease, Ebola was first observed 1976 and has since impacted thousands of humans and animals, primarily in Central Africa.

“Inflammation of the eye, known as uveitis, is very common following infection with Ebola and we know the cells within the iris, at the front of the eye, as well as the retina have the capacity to play a major role in uveitis and act as hosts for microorganisms,” says study senior author Dr Justine Smith, a strategic professor in Eye and Vision Health at Flinders University. “However, what we didn’t know was which out of the two was most responsible in the case of Ebola.”

The study was led by Flinders University and CSIRO’s Australian Centre for Disease Preparedness, used cells from human eyes donated from the SA Eye Bank to investigate the ability of iris and retinal pigment epithelial cells to be infected by Ebola.

According to a news release from Flinders University, cells were infected with Ebola virus, Reston virus (a type of 

 that does not cause disease in humans) or Zika virus (another type of virus, but one that also can cause uveitis), while some were left uninfected for the duration of the trial.

While both types of cells seemed to allow the Ebola virus to replicate, it was the retinal cells that showed much higher levels of infection.

“We also found similar results when looking at the cells infected with Reston virus and Zika virus,” Dr Smith said in the release.

Moreover, Dr Smith explained that patients with Ebola eye disease have characteristic retinal scars, suggesting the retinal pigment epithelium is involved in the disease, so this finding is consistent with what eye doctors are seeing in the clinic.

“These retinal cells are good at eating things – called phagocytosis - and they play an essential part in the visual cycle by recycling our photoreceptors, so it makes sense that these cells would be a receptive haven for Ebola, as well as other viruses,” she noted.

According to the university, the researchers explained that the study demonstrates an important target cell for Ebola infection in the eye and suggests the potential for these cells to be monitored during acute viral infection to identify patients at highest risk of uveitis.

“Amongst other issues, including pain and blurred vision, uveitis can ultimately lead to vision loss, so it’s important we find ways to diagnose it as early as possible to enable swift treatment,” Dr Smith concluded.

The work was supported by a grant from the National Health & Medical Research Council.

1. Shawn Todd, Yuefang Ma, Liam M. Ashander, Binoy Appukuttan, Michael Z. Michael, Timothy A. Blenkinsop, Steven Yeh, Glenn A. Marsh and Justine R. Smith

Ebola virus differentially infects human iris and retinal pigment epithelial cells. Frontiers in Virology

A team of investigators at Flinders University in Australia have found that a specific cell within the retina appears to be particularly good at housing Ebola and other viruses.

Ebola, other viruses may be housed in retina cells

 shared video interviews with Dr Karl Csaky, Dr Harry Flynn, Dr Sally Tucker, Nancy Lurker and Dr Penny Asbell. The breadth of their collective expertise spans from geographic atrophy to endophthalmitis and antiobiotic resistance and back to retinal therapies. Dr Sally Tucker of Ora Europe provides an inside look at how they design clinical trials to be safe, effective and scientifically sound.

Additionally, there was a discovery that diet, eye health and lifespan may be linked. According to investigators, a key reason for the link may lie in circadian “clocks,” the molecular machinery within every cell of every organism, which have evolved to adapt to daily stresses, such as changes in light and temperature caused by the rising and setting of the sun.

Is retinal tissue preservation as important as decreased GA expansion in future therapies?

As novel therapies in the pipeline are aiming to decrease the rate of GA expansion—the endpoint Dr Karl Csaky and Dr Fredrick Ferris III identified in 2007—Dr Csaky reinforces the importance of preserving the central retinal tissue.

Approaches for managing treatment of patients with endophthalmitis

Via four cases, Dr Harry Flynn describes a variety of endophthalmitis management options for retinal surgeons.

Link discovered between eye health, diet and lifespan

A team of investigators at the Buck Institute have unveiled a link between eye health, diet, circadian rhythms and lifespan in 

According to a news release from Buck Institute, the study was published in a recent issue of 

The news release noted that previous studies have shown in humans that there is an association between eye disorders and poor health.

“Our study argues that it is more than correlation: dysfunction of the eye can actually drive problems in other tissues,” said Dr Pabjaj Kapahi, a lead author of the study. “We are now showing that not only does fasting improve eyesight, but the eye actually plays a role in influencing lifespan.”

“The finding that the eye itself, at least in the fruit fly, can directly regulate lifespan was a surprise to us,” co-lead author, Brian Hodge, PhD, who did his postdoctoral studies in Dr Kapahi’s lab, said in the news release.

Ora Europe executive outlines pathway for clinical trials

Dr Sally Tucker of Ora Europe walks through the clinical trial pathway, describing how Ora addresses complexities to make the path as efficient as possible.

Treat-to-maintain drug vorolanib ushers in new era for retinal therapy

During the Retina Unplugged panel at Retina World Congress, Nancy Lurker presented on new pathways in retinal diseases. She outlined how EYP-1901, EyePoint Pharmaceuticals’ candidate for the new treat-to-maintain paradigm they hope to begin. EYP-1901 combines vorolanib, a tyrosine kinase inhibitor anti-VEGF, with a bioerodible retinal implant (Durasert, EyePoint Pharmaceuticals). Nancy Lurker is the CEO of EyePoint Pharmaceuticals.

ARMOR study: Evaluating antibiotic resistance in the treatment of staph infections

Dr Penny Asbell discusses her presentation entitled, “Antibiotic Resistance among Ocular Staphylococcal Pathogens: Longitudinal Trends in the ARMOR Study."

An end-of-week review of what happened in ophthalmology from 18 June to 24 June.

Weekly review in ophthalmology: 18 June - 24 June

At Retina World Congress 2022, Dr Karl Csaky presented a talk entitled, “Interpreting Reported GA Treatment Effects to Patient Care: Concept of Tissue Preservation.” He discussed how far research in geographic atrophy has come since he embarked on a project to determine provable endpoints for geographic atrophy (GA) in 2006 and 2007. Now that treatments in the pipeline are aiming to decrease the rate of GA expansion—the endpoint Dr Csaky and Dr Ferris identified in their research—he doubles down on the importance of preserving the central retinal tissue.

Dr Karl Csaky serves as the T. Boone Pickens Director of the Molecular Ophthalmology Laboratory and Clinical Centre of Innovation for Macular Degeneration. Additionally, Dr Csaky is the Chief Executive and Medical Officer at Retina Foundation of the Southwest.

What we're trying to do is, you know, many years ago, I led with Rick Ferris, and a symposium with the Food and Drug Administration on endpoints for various trials and retinal diseases. And back in 2006-2007, we worked on and came to an agreement that the decrease in the rate of GA expansion could be a provable endpoint. And that's been now the gold standard in the community.

And here at this meeting, and throughout other meetings, we are hearing about treatments that may be achieving that endpoint. However, when we really think about what's critically important for patients, while reducing GA expansion is definitely a way to assess the therapy overall, what I was trying to focus this talk on is the what's critical for patients. And for patients. It's really the central retinal tissue within the macula and fovea that needs to be preserved.

So when we think about these therapies potentially coming to the clinic, we really need to be thinking about them in a slightly different, more focused approach. Which is trying to understand as we apply these treatments: How much truly important, critical tissue is being preserved? Which will allow for the patients to have better outcomes in terms of driving, seeing and reading. And so this talk is simply a focus on that subject.

Note: This transcript has been lightly edited for clarity.

Videos

At Retina World Congress, Dr Harry W. Flynn presented a series of videos that illustrated vitrectomy techniques in endophthalmitis management cases. In the four cases he presented, Dr Flynn described a variety of endophthalmitis management options for retinal surgeons.

Thank you. I was part of a symposium on uveitis, and I was specifically talking about endophthalmitis management approaches. My focus was on vitrectomy techniques in the management of endophthalmitis cases.

I started out with a case of endogenous endophthalmitis caused by 

. The traditional way of handling these cases is to perform a pars plana vitrectomy. But many of these eyes are prone to retinal detachment because of vitreoretinal traction. And because of large lesions that have organisms growing through the choroid into the retina and into the vitreous, these lesions are often highly elevated.

In a video, I showed a technique of laser treatment to surround the lesions first, and then to actually obliterate the lesion with direct focal laser. We still use intravitreal and systemic antifungals as part of the treatment.

My second case was a bleb-associated endophthalmitis, and I show 27-gauge vitrectomy techniques to enter the eye, especially when these eyes are very congested, and to remove the vitreous and allow injection of intravitreal antibiotics. It is important to avoid de-bleeding the bleb because these blebs are highly necrotic. And if you do so, the debris mot will leave a large hole in the sclera often with leakage…very difficult to close. So we just use subconjunctival antibiotics in these cases, which are usually adequate.

My third video was on a combined approach to keratitis-associated endophthalmitis. These cases are particularly tough because the cornea is opaque. There is no view of fundus details. So I showed a combined approach with 25-gauge surgery, a corneal transplant, removal of the intraocular lens, performance of a pars plana vitrectomy, and placement of fresh corneal tissue graft in place when finally with injection of individual antibiotics.

My last case was a suture removal-related endophthalmitis. These cases occur rarely, but they do occur when people forget to use povidone iodine on the ocular surface. And these are often caused by 

 which is a very virulent organism, and it causes poor outcomes. I showed a technique of using 27-gauge vitrectomy in the anterior chamber to remove the fibrin clot, followed by a pars plana vitrectomy. again using 27-gauge techniques. The pictures that I showed were courtesy of David Jacobs, one of my former fellows who allowed me to use his slides.

In summary, I used my presentation as a way to present vitrectomy approaches for endophthalmitis in these very difficult and challenging cases.

According to Hodge, a key reason for the link may lie in circadian “clocks,” the molecular machinery within every cell of every organism, which have evolved to adapt to daily stresses, such as changes in light and temperature caused by the rising and setting of the sun. These 24-hour oscillations - circadian rhythms - affect complex animal behaviours, such as predator-prey interactions and sleep/wake cycles, down to fine-tuning the temporal regulation of molecular functions of gene transcription and protein translation.

According to the institute’s news release, in 2016 Dr Kapahi’s lab published a study in 

 showing that fruit flies on a restricted diet had significant changes in their circadian rhythms in addition to extending lifespan.

When Hodge joined the lab later that year, he wanted to dig deeper to figure out which processes that enhance circadian functions were altered by the diet change, and whether circadian processes were required for the longer lifespan seen with dietary restriction.

“The fruit fly has such a short lifespan, making it a really beautiful model that allows us to screen a lot of things at once,” Hodge, who is currently a scientist at Fountain Therapeutics in South San Francisco, said in the news release.

The study began with a broad survey to see what genes oscillate in a circadian fashion when flies on an unrestricted diet were compared with those fed just 10 percent of the protein of the unrestricted diet.

Hodge quickly noticed numerous genes that were both diet-responsive and also exhibiting ups and downs at different time points, or “rhythmic.” He then discovered that the rhythmic genes that were activated the most with dietary restriction all seemed to be coming from the eye, specifically from photoreceptors, the specialized neurons in the retina of the eye that respond to light.

This finding led to a series of experiments designed to understand how eye function fit into the story of how dietary restriction can extend lifespan. For example, they set up experiments showing that keeping flies in constant darkness extended their lifespan.

“That seemed very strange to us,” Hodge said in the release. “We had thought flies needed the lighting cues to be rhythmic, or circadian.”

They then used bioinformatics to ask: Do the genes in the eye that are also rhythmic and responsive to dietary restriction influence lifespan? The answer was yes they do.

“We always think of the eye as something that serves us, to provide vision,” Dr Kapahi, also an associate adjunct professor of urology at UCSF, said in the news release.

Since the eyes are exposed to the outside world, Dr Kapahi noted in the release, the immune defences there are critically active, which can lead to inflammation, which, when present for long periods of time, can cause or worsen a variety of common chronic diseases. Additionally, light in itself can cause photoreceptor degeneration which can cause inflammation.

Dr Kapahi also noted that extended time viewing computer and phone screens and being exposed to light pollution well into the night are conditions very disturbing for circadian clocks.

“It messes up protection for the eye and that could have consequences beyond just the vision, damaging the rest of the body and the brain,” he said in the release.

There is much to be understood about the role the eye plays in the overall health and lifespan of an organism, including: how does the eye regulate lifespan, and does the same effect apply to other organisms?

A key question posed by the work as it could apply to humans is whether photoreceptors in mammals affect longevity?

Hodge pointed out that it is probably not as much as in fruit flies, since a large portion of the energy in a fruit fly is devoted to the eye. But since photoreceptors are just specialized neurons, he said, “the stronger link I would argue is the role that circadian function plays in neurons in general, especially with dietary restrictions, and how these can be harnessed to maintain neuronal function throughout aging.”

Once investigators understand how these processes are working, they can begin to target the molecular clock to decelerate aging, Hodge noted, adding that it may be that humans could help maintain vision by activating the clocks within our eyes.

“It might be through diet, drugs, lifestyle changes … A lot of really interesting research lies ahead,” he concluded.

1. Pabjaj Kapahi, PhD; Brian Hodge, PhD; et.al; Dietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila. Nature, published June 2022. DOI: 10.1038/s41467-022-30975-4

According to investigators, a key reason for the link may lie in circadian “clocks,” the molecular machinery within every cell of every organism, which have evolved to adapt to daily stresses, such as changes in light and temperature caused by the rising and setting of the sun.

In Denver, Colorado, United States, Dr Sally Tucker, vice president of Ora Europe, describes the complexities that Ora overcomes when designing clinical trials.

Hello, my name is Sally Tucker, and I am the vice president of Ora Europe, overseeing all of our clinical operations across the European region. So as we consider the pathway to the approval of any products, we need to consider the complexities and how we address those to make the pathway as efficient as possible. The aim of this is to speed the time to approval for the products that you bring to market.

The complexities that we face increase the larger the trial, and this is something that we need to address particularly when we are thinking about larger Phase 3 trials in which more patients are required, and in which there's often a requirement to think about global site outreach.

So how can we do these things? The first is through protocol design. We need to consider within the protocol what are the requirements of the regulators. We have experience working with regulators across the globe, the FDA, the EMA, the MHRA, the Chinese FDA, and the PMDA. We will address the regulatory requirements and make sure that they are within the protocol design, depending upon which country approval you are seeking.

The second thing that we need to consider in the protocol design outside the regulatory requirements is whether the protocol is clinically executable. It is really important to engage with investigators across the globe to make assessments of the protocol. Does the protocol makes sense? Can it be done within a clinical setting? And we also need to consult with patients. And this is something that we take great pride of doing. We have numerous patient panels, and we consult with these patient panels. How does the protocol design look? Is it too burdensome for the patient? Are we addressing their hopes, their desires, and also their concerns and fears to increase the likelihood for them to want to be a part of the research and the clinical trial?

The next thing we need to consider is the slight outreach, especially in these large Phase 3 trials in which we might have to consider multiple countries. We need to consider the patient demographics, and where the patients are to be found. (We also consider) the competitive environment and the standard of care health care provision in the country that we approach.

How can we elevate research as a care option to patients to optimize recruitment? We also work with the sites and the investigators themselves who work tirelessly on these clinical trials, helping to bring these projects and these product products to market. How can we support them better - training of staff coaching mentorship, collaboration across sites, feeling that they're part of something bigger, broader? And how can we also assist with pre-screening, helping to identify patients to bring to the sites to speed the overall execution of the clinical trial?

The last aspect that we also consider is our patients. We as scientists, investigators, clinicians, researchers, put patient at the centre of all we do we all want to make a difference to the patients that we serve.

So how can we best do that? We have patient panels that we work with, identifying how we can make the protocols less burdensome for them, and how we can support them on their journey, being a part of the clinical trial, and how we can develop patient facing materials that address their needs. And also engage with them throughout the duration of the clinical trial in a compassionate and empathetic manner so that they feel engaged.

They are reminded why they are in the trial, and they are appreciated for being in the trial. We are committed to all of the stakeholders that we work closely with the companies that work tirelessly to bring novel new products to market that can address the unmet needs of patients, to the sites who work so hard and conducting the clinical trials and the patients for whom we all serve. Thank you.

Ora Europe executive outlines pathway for clinical trials 

Sheryl brings a wealth of editorial experience to MJH Life Sciences’ Eye Care Network, having engaged with the readers and the greater ophthalmic community of 

for more than 20 years. As Group Editorial Director, Sheryl’s purview extends across the print and digital network of 

Ophthalmology Times, Ophthalmology Times Europe, Modern Retina 

 Prior to ophthalmology, Sheryl previously covered the fields of audiology and confectionery science/technology/manufacturing.

Sheryl is also passionate about the mission, vision and values of Ophthalmic World Leaders (OWL) and recently completed her term on its Board of Directors. She continues to volunteer as Editor-in-Chief of the organization’s 

Magazine. In 2013, she was honored with the group’s inaugural Rising Star Award.

In addition, she has served as a judge for 

 Health Care Heroes Awards program as well as the Jesse H. Neal National Business Journalism Awards.

Dr Sunir J. Garg discusses the benefits of hypersonic vitrectomy as a novel technologic advancement for retinal surgeons in a presentation at the 2022 Retina World Congress.

Yeah, so hypersonic vitrectomy is one of the really most novel ways we have of removing vitreous, and our traditional guillotine cutters are really amazing. And as they've gotten faster and faster, they take smaller bites of the vitreous gel. And as you take smaller bites of the vitreous gel, you reduce viscosity. When you have less viscosity, you're able to remove the gel a lot more efficiently.

And over the past 10 to 15 years, our cutters went from 2500 cuts a minute to 15,000 cuts a minute to getting closer to 30,000 cuts a minute. But there's certain inherent limitations. Smaller bites are still small bites, but they're not tiny particles.

One of the other limitations of our standard guillotine cutters is they're a needle and needle design. And as you may remember from high school physics, the smaller you make a lumen, the exponentially more resistance you have. Hypersonic vitrectomy not only takes small little particles of the vitreous gel, but it doesn't have a needle and needle design. So the single lumen gives you an effectively larger internal radius, enabling you to remove the vitreous gel a lot more efficiently.

So we looked at a bunch of different cases using this technology. And we found that we could do pretty much a whole host of retinal surgeries with it: retinal detachments, retain lens material, silicone oil cases. And for a lot of cases, it was really great. And surgeons found that was particularly advantageous for removing vitreous gel in mobile retina. So in retinal detachment cases it was terrific. We could use that same port to remove retain lens materials, we didn't have to open up a frag in these cases. And some of my colleagues actually used it to remove silicone oil.

And it was kind of neat to be able to do basically the entire surgery with one instrument. There was a couple of cases in which I don't think anything's going to be better than a guillotine cutter, particularly in really thick, dense diabetic membranes. Using scissors or guillotine cutters are really fabulous. And there's a couple of cases that had a really kind of glassy, thick vitreous gel, that this didn't work that great, but honestly, neither did my guillotine cutter so I think that was just those cases.

One of the other potential advantages of this is you don't need gas, so you don't need big gas tanks and you don't need to be tethered to an operating room. So whether you're in places around the world that don't have easy access to those things, or whether you're looking at doing vitrectomy outside of the traditional or this might be really advantageous.

There are some limitations about it, you know, we're still refining the different port technologies. So one of the great things about this is you can change the port. So you can make it into a teardrop shape; you can make it into a sigmoid shape, and some of our new iterations seem to be a lot more efficient than our old ones.

We're also adjusting some of the parameters of the handpiece. One of the things that we found is by increasing the frequency, we can dramatically increase the force or the ability of the instrument to cut the vitreous gel. And we're currently working on a new sigmoid shape, which seems to be a major improvement over what we had before.

But considering that the technology is really new, and there's only been hundreds or maybe 1,000 cases done, I'm really impressed with how dramatically better the technology continues to get. And as we use it more often, I think we'll continue to refine it.

Though the speed of traditional guillotine cutters has increased significantly in recent years, there are certain limitations. With the advent of hypersonic vitrectomy, Dr Sunir J. Garg explains how retinal surgeons can remove the vitreous gel with more efficiency.

Hypersonic vitrectomy a novel technology for removing vitreous

Rishi P. Singh, MD, FASRS, highlights the two-year results of the YOSEMITE and RHINE trials, in which patients were randomized to receive either faricimab or aflibercept, in a presentation at the 2022 Retina World Congress.

My presentation was on the two-year results of the YOSEMITE and RHINE trials. This trial enrolled patients and randomized them to receiving either faricimab or Eylea within the course of the trial. The patients in the faricimab arm were actually given either a personalized treatment approach after four loading doses or given the drug every eight weeks after loading period.

And what the study found was really quite interesting. The faricimab molecule, which is both a combined anti-Ang2 and an anti-VEGF, performed better than the aflibercept drug in the trial in many different ways.

First and foremost, the durability of the drug was significantly better in the faricimab study, with almost 79% of patients achieving acute 12 week of dosing and the personalized treatment approach during the end of the two-year study.

In addition, 60% of patients who received the drug every 16 weeks at the end of the two-year trial, and we found greater reductions in retinal fluid, especially intraretinal fluid, within the faricimab arm compared to aflibercept. As well as we saw better resolution of diabetic macular edema in a faster fashion within the faricimab arms compared to aflibercept during the two-year trial.

In the study, the faricimab molecule, which is a combined anti-Ang2 and anti-VEGF, performed better than the aflibercept drug in many different ways. Rishi P. Singh, MD, FASRS, summarizes some of these key findings.

Significance of the YOSEMITE and RHINE 2-year DMO clinical trial results

Self-Plugging needles provided a more targeted, self-plugging drug delivery. (Image courtesy of Terasaki Institute for Biomedical Innovation)

A team of investigators, including scientists from the Terasaki Institute for Biomedical Innovation (TIBI), has developed a novel, self-plugging microneedle for injecting therapeutics into the eyes, potentially solving one of the major challenges of treating eye diseases—accurate delivery of therapeutic drugs to the retina, while guarding against possible complications at the injection site.

According to the institute, in a recent study,

 investigators found preclinical evidence that this innovative, biodegradable microneedle, dip-coated with a therapeutic drug for release upon insertion into the eyeball, can also be equipped with a special hydrogel that simultaneously seals off the insertion hole. Additionally, this self-plugging microneedle can be fabricated with different needle lengths, so therapeutics can be precisely targeted and dispersed to retinal tissues or other areas within the eyeball.

“This novel improvement in drug delivery treatment can avoid problems associated with using needles to treat serious eye diseases,” Dr Ali Khademhosseini, TIBI’s director and CEO and a co-author of the study, said in a news release from TIBI. “It is one of many simple, yet effective and impactful innovations from our institute, which is focused on translating biomedical engineering into clinical realities.”

The challenge – and need – for retinal drug delivery

The retina is a thin layer of cells that make up the inner lining of the very back of the eyeball. It enables vision by receiving light and converting it to signals that travel to the brain, which then interprets them as images.

As vital as it is to clear, crisp vision, the retina and its critical central portion, the macula, are also subject to different types of damage due to age, genetics, disease and other risk factors. This damage can cause symptoms ranging from distorted or seriously impaired vision to complete blindness and can be widespread among different populations. Indeed, age-related macular degeneration is the leading cause of irreversible vision loss in adults aged over 60, and diabetic retinopathy is the leading cause of blindness among U.S. working-aged adults aged 20 to 74 years.

According to TIBI, some forms of retinopathy can be treated by the injection of drugs into the eyeball using syringes and hypodermic needles. In this procedure, the injected drugs diffuse through the fluid within the eyeball to reach the damaged site. In many cases, multiple injections are needed over a prolonged period of time in order to protect their vision. In addition to this regimen being a hardship on patients, it introduces the risk of bacterial infection at the needle withdrawal site. It can also pose a risk for floating tumour cells in diseased eyes to escape through the puncture holes and migrate to other sites.

TIBI noted in its news release that in order to avoid these hurdles, implantable needles have been attempted for drug delivery. However, mechanical difficulties and navigation through the viscous fluid in the eyeball have hampered accurate needle placement and pose an additional risk of retinal damage. Other approaches involve polymer plugs to close the holes left by hypodermal needles, but this involves a separate step and time lag after injection.

According to TIBI, different types of microneedles, both in singular or patch form, have proven effective for drug delivery into different regions of the eye, with minimal puncture size and optimally targeted drug delivery. A collaborative team, including scientists from the Terasaki Institute for Biomedical Innovation, has built upon this technology by developing a novel, self-plugging microneedle for advanced injection treatment of the eyes.

The TIBI team utilized a precision fabrication method to create biodegradable, sharp-tipped, ultrathin microneedles of various lengths. This versatility in needle length allowed for a more controllable placement into the eyeball and more accurate drug delivery to the injury site; the fineness of the needles minimize incision size in the eyeball. The sharp end of the needle could be dip-coated with the therapeutic drug, with the needle releasing the drug upon insertion into the eyeball.

As an innovative addition, the blunt end of the microneedle was affixed with an experimentally optimized hydrogel plug, which could swell after needle injection and seal off the insertion hole.

The 2 microneedle coatings were examined microscopically and tested for strength before subjecting them to validation tests for drug delivery and sealing effectiveness. Initial 

tests using the drug-loaded microneedles demonstrated almost complete drug delivery over a 24-hour period; similar experiments using dye-loaded SPNs inserted into vials of pig eyeball fluid demonstrated dye release over a suitable distance for injection into the eyeball.

 experiments measuring the internal pressure of cultured pig eyeballs showed that there was almost no change in pressure after applications of SPNs, unlike the pressure drop obtained when non-plugging microneedles were applied. Examination of the tissue at the SPN application site confirmed firm attachment of the SPNs.

 experiments measured dye-tracked release from the SPNs into cultured rabbit and pig eyeballs. Tissue sections from these eyeballs revealed that dye distribution distance from the insertion site was directly proportional to needle length, demonstrating the spatially controllable drug delivery capabilities of the SPNs.

 on pig animal models. Seven days after application of dye-loaded SPNs to the pigs’ eyes, observation through the pigs’ corneas revealed that the SPNs were still firmly implanted and there was no needle deformation. Leakage tests using surgical sponges showed no leakage of eyeball fluid.

TIBI noted in the news release that tissue section staining of the eyeballs exhibited complete dye dispersal and deep penetration into retinal tissues. Notably, there were no signs of inflammation or tissue disruption at the application site.

This work was supported in part by a grant by the National Research Foundation of Korea (NRF), a grant funded by the Korean government (MSIT) (2021R1F1A105502211), and the Basic Science Research Program through the NRF, funded by the Ministry of Education (NRF-2017R1A6A3A04004741.

1. Kang Ju Lee, Seung Hyun Park, Dong Hyun Jo, Chang Sik Cho, Ha Young Jang, Jiyeon Yi, Minkyung Kang, Jaeho Kim, Ho Yun Jung, Jeong Hun Kim, Won Hyoung Ryu, and Ali Khademhosseini. Self-Plugging Microneedle (SPM) for Intravitreal Drug Delivery. 

. Published February 22, 2022. doi: 10.1002/adhm.202102599.

In a recent study, investigators found preclinical evidence that this innovative, biodegradable microneedle, dip-coated with a therapeutic drug for release upon insertion into the eyeball, can also be equipped with a special hydrogel that simultaneously seals off the insertion hole.

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Self-plugging microneedles may improve drug delivery in the eye