In January 2nd’s Episode (LINK), Jay was joined by Dr. Allen Ho to discuss his recently published paper in Nature Medicine regarding the successful use of an intravitreal oligonucleotide for a form of Leber Congenital Amaurosis (LCA). Dr. Matthew Weed then joined the podcast to discuss the article and compare previously used therapies like Luxturna. In this post we are going to review what Leber Congenital Amaurosis is and how this new oligonucleotide functions to rescue one of the mutations that causes LCA.

Leber Congenital Amaurosis is a genetic disorder that primarily affects the retina leading to visual impairment beginning in infancy. Patients suffering from this disorder can also have nystagmus, photophobia, and slow pupillary reactions. Visual impairment begins in early childhood, and progressively deteriorates ultimately resulting in vision loss at around thirty to forty years old. This disorder is inherited primarily in an autosomal recessive pattern. Mutations in at least 14 genes have been identified, with the most common being CEP290, CRB1, GUCY2D, and RPE65. You may have read or listened to our recent discussion on the use of gene therapy for RPE65 (LINK TO PODCAST AND BLOG). The article discussed in Episode 147 focused on CEP290, which is a gene that plays an important role in the development of centrosomes and cilia. The most common mutation in CEP290 that leads to LCA causes a splicing error in pre-mRNA. The mutation, which changes an adenine to a guanine, occurs within one of the introns of CEP290. This creates a new splice-donor site and a new exon (Exon 10) is aberrantly inserted into the final mRNA. This new exon carries a premature stop codon that, when translated, results in a truncated CEP290 protein that no longer functions as the original protein.

An antisense oligonucleotide (ASO) is a short (generally 13-25 nucleotides) single-stranded DNA molecule that can hybridize to a unique target sequence in a cell. The first generation of ASOs were designed to target mRNA and thereby knockdown the transcript via endonuclease-mediated degradation. These agents had the disadvantage of fast turnover, which prohibited them from achieving intracellular concentrations sufficient to suppress their target. New ASOs have been developed with modified backbones that function through different mechanisms like preventing ribosome recruiting to inhibit translation, or sterically blocking splicing factors to alter pre-mRNA splicing.

Image credit: https://rockland-inc.com/anti-oligonucleotide-antibodies.aspx

The ASO (QR-110) used in the paper discussed in Episode 147 works by modifying splicing in a slightly different manner than described above. QR-110 binds to the CEP290 pre-mRNA at the intron that contains the mutation. This binding prevents the creation of a new splice site, which causes the pre-mRNA to be processed as the wild-type pre-mRNA, without the inclusion of Exon 10. The protein translated from the mRNA is a wild-type CEP290 protein that can function normally in the development of centrosomes and cilia.

Image credit: https://www.nature.com/articles/s41591-018-0295-0#Fig1

          -Amy Kloosterboer

For the final episode in 2018 (LINK), Jay was joined for Journal Club by Drs. Daniel Chao and Ajay Kuriyan to discuss 3 recent publications: first the PIVOT trial comparing primary vitrectomy and pneumatic retinopexy, then the FLUID study looking at the effect of residual SRF in wet AMD, and finally a study out of Stanford University looking at timing of macula-off retinal detachment repair.

All three articles measured visual acuity as an outcome but did so utilizing different methods. The PIVOT and FLUID trials used ETDRS logMAR chart, and the macula-off retinal detachment repair study used a Snellen chart. Visual acuity, the ability to resolve spatial objects, is a common chosen endpoint of many clinical studies. In this post we will discuss how the methods used to measure it were developed and subsequently improved upon.

Image credit: https://en.wikipedia.org/wiki/Snellen_chart

The Snellen chart is an iconic image nearly ubiquitous in the doctor’s office. It was created by Dutch ophthalmologist Dr. Herman Snellen in 1862. After his colleague, Dr. Franciscus Donders, had started to diagnose vision problems by asking patients to gaze at a card in a distant wall, he asked Dr. Snellen to help him develop a tool for this purpose. The original chart had shapes of various sizes including squares, circles, and plus signs. This proved to be challenging to use since the patients had to describe the symbols they saw. To simplify the process, letters eventually replaced symbols, giving way to the Snellen chart we use today. It is composed of eleven lines of capital letters that decrease in size as you progress down the rows. The patient is asked to stand 20 feet away from the chart, cover one eye, and read from it without using glasses. The top number seen on the ratio next to the letters represents the distance from the chart, and the bottom number is the distance at which a person with “normal” eyesight can read that same line. A person with normal visual acuity should be able to correctly read line 8 at a 20 feet distance from the image.

The logMAR chart (Logarithm of the Minimum Angle of Resolution) is another chart utilized to test visual acuity in patients and was developed in 1976 at the National Vision Research Institute of Australia. It was designed to be more accurate than the Snellen chart, and therefore, it is commonly used in research. The design allows for a logarithmic or proportional change in the letter size and spacing as it is read. It also improved on some of the previous concerns regarding the Snellen chart. The logMAR chart, unlike the Snellen, has the same number of letters in each line, each with the same degree of difficulty. To test visual acuity using the logMAR method, the patient is asked to stand 4 meters away (13.14 feet) from the chart. Each letter has a score of 0.02 log units, for a total change of 0.1 log units per line. A person with “normal” eyesight should receive a logMAR score of zero, while those with poor vision will receive a positive number.

-Amy Kloosterboer

Image credit: https://www.precision-vision.com/product/4meteroriginalseriesetdrschart2/

As we ring in what will be our 3rd full year of releasing episodes of Straight From The Cutter’s Mouth: A Retina Podcast, I would like to start by taking a moment to thank a few people who make possible our weekly episodes releases.

First, Dr. Louie Cai is our webmaster extraordinaire, incredible producer, and technological Swiss army knife who keeps our endeavor a well-oiled machine. It is not hyperbole to say that he is one of the most important people to ever enter my life. Angela Chang is an audio editing machine who is quiet and unassuming and deserves major credit for taking our moderate quality recordings and turning them into the polished product hitting your phone every week. Mike Venincasa handles our social media distribution on Facebook and is our main contributor to the blog, where he has started a new project with our latest recruit, Amy Kloosterboer. Many of our episodes would be impossible without frequent contributors like my colleagues Dr. Ajay Kuriyan (podcast MVP three years running), Dr. Daniel Chao, Dr. M. Ali Khan, Dr. Will Parke, and the others who I bother week after week to join me on conference calls at odd hours built around multiple busy retinal surgeon schedules. Finally, it may sound corny every time I state this at the end of each episode, but all of the people who listen and tell their friends, colleagues, and trainees to listen make this experience special. It is the ideas and thoughts of listeners that continue to keep us fresh and motivated with new and thoughtful episode ideas.

Listeners and others ask frequent questions about our podcast, and I will use this blog post to both answer some frequently asked questions (FAQs) and transparently address some of the recent changes surrounding our project:

Why did you start the podcast?

We have addressed this in a few of our ‘state of the podcast’ episodes, but to summarize: leaving fellowship I anticipated joining a job that involved significant commuting, as many surgical retina jobs do. As a newly minted podcast consumer in other disciplines, I searched for a retina resource that could be educational on the go and came up mostly empty. One of my faculty mentors suggested that I pursue such a project myself, but it was not until months later when my friend Dr. Will Parke suggested that I pursue it as a solo venture that we got started. I spent a week reading about podcasting and audio recording on the Internet, obtained the necessary equipment, website, and software, figured out how to release via iTunes and social media, and then released the first episode on November 1st, 2016. It became immediately apparent that a completely solo venture would be impossible as my clinical and academic obligations continued to evolve, and within two weeks Louie Cai was on board running the website and producing the episodes. The rest is history as both our team and listener base have grown steadily over two plus years.

What about money? Who pays you to do the podcast?

Nobody. Making money off the podcast is a concept many friends and colleagues have asked me about, but it was never a primary motivation. Our team has discussed this issue multiple times, and to this point we unanimously have agreed to keep the podcast focused on a different goal: releasing useful, educational, consumable, permanent content that can be both a current resource and a repository of retina knowledge for years to come.

What about your costs?

Maintaining the website is roughly $100/year, software/audio licenses another approximate $250/year, and equipment averages $500/year to this point. Recently we have added legal protections with costs of about $3000. There are certainly major times costs to what we do as well. I have independently covered these costs through the end of 2018.

What about Retinal Physician, ASRS, and AAO? How are they supporting you?

We have been extremely grateful to these organizations for their support, but to answer a common question, none of that support has been or will be financial. Retinal Physician provides us their article proofs in advance so we can record periodic episodes that are different than our normal journal club episodes in allowing our contributors to take discussion in different and more creative directions. The American Society of Retinal Specialists (ASRS) generously offered to upload our episodes in a special podcast section of their website for members as a resource. The American Academy of Ophthalmology (AAO) is uploading and posting our episodes on their website as a free resource as well, with the upcoming added benefit of continuing medical education (CME) credits for certain episodes.

When will the CME be available? What about financial disclosures?

Probably early in 2019. The team at AAO has worked tremendously hard to obtain CME not only for the new episodes but for past episodes that qualify. As soon as we have details we will post prominently on the website and mention in the episodes themselves.

In preparation for the CME transition we are now including financial disclosures for all contributors to each podcast episode. Even if this was not required by CME, we were moving in this direction, as transparency in this day and age is paramount.

How do you plan to cover your costs going forward?

We are initiating a few new ventures. First, similar to Wikipedia and other free online resources we will soon be placing buttons on the website for people to contribute small dollar amounts either one time or monthly to support the podcast. Second, we are investigating making and selling podcast ‘swag’ including T-shirts and other apparel for the loyal supporters who have asked. Third, we will be rolling out limited advertisements before and after episodes, although I have an extremely strong preference to avoid ‘mid-roll’ advertisements that disrupt the flow of the episode/conversation.

What about these future advertisements? Isn’t that a conflict of interest?

Industry is critical to the development and advancement of our field, and myself and many others who contribute on the podcast have industry ties and disclosures. That being said, we have and still will continue to try and avoid any industry (pharmaceutical or surgical device) advertisements on our program. One of the things that makes doing the podcast so enjoyable is the freedom of discussion and we think staying industry-free helps maintain that environment.

We will be rolling out our first ever paid episode advertisement in Episodes 148-151 on behalf of a retina-only private practice looking for a new associate on partnership track. The practice approached us with the idea and I accepted. I felt comfortable with this decision for a couple of reasons. First, a job recruiting advertisement has no effect or influence on the resulting discussion. Second, the practice has a positive reputation and may actually represent a great opportunity for one of our listeners. Will we pursue similar advertisements in the future? Probably and hopefully, but I think that those decisions will be made on a case by case basis.

What if your new revenue streams exceed your costs? Who pockets the surplus?

Nobody. Surplus revenue will be directed towards either improving or adding to our recording equipment to allow us for more creative episodes (for example, high quality group interviews at major meetings) or future travel grants/scholarship opportunities for residents and fellows to attend major meetings.

So how many people listen now? What other podcast-related activities are you pursuing?

We have tremendously fortunate to see a steady and ascending base that listens to our episodes consistently. For the first few episodes we averaged 50-100 unique listeners/episode. At the end of 2017 it was closer to 300 listeners/episode. But now at the end of 2018 we are up to about 1000 listeners/episode. Given how niche and specialized our program is, that is a tremendous number! More encouraging is that if we examine the statistics for ‘old’ episodes unique listeners keep going back and listening, meaning we are achieving our goal of releasing content that is current but still useful months to years later.

We have written a couple of upcoming papers on our podcast data and a survey we collected last year. We will also be collecting a larger survey this year and will be presenting research at major meetings such as the AAO annual meeting and AUPO annual meeting (Mike Venincasa), the Innovations in Medical Education conference (myself), and others pending acceptance (Louie Cai, Angela Chang). We believe that our experience has reinforced what other medical specialties had discovered before us: podcasts and mobile audio learning are the present, not the future. Our research is designed to emphasize that.

My co-resident loves your podcast but is going into glaucoma. Will you do a podcast about glaucoma? What about cornea?

I have been asked this multiple times and am always honest that my relative knowledge base would limit my ability to host a topical and interesting show and ask guests the right questions. We are investigating the possibility of a producing a ‘sister’ anterior segment show, but it has to have the right host, environment, and consistency to not dilute from what we are doing on the retina side. TBD!

Hopefully that answers many of the questions that have come up and will come up going forward. Happy new year and thank you!

                                                                                                                                         Jay Sridhar

(Left) Dr. Elizabeth Sargent and (Right) Isabel Hayes Chapin Barrows. Image Credit: https://www.aaojournal.org/article/S0161-6420(14)01093-8/fulltext

            In this week’s Episode (LINK), Jay was joined by Drs. Zelia Correa, Geeta Lalwani, and Ashvini Reddy for a panel discussion about the job and contract negotiation process, with a special focus on maternity and sick leave. Therefore, we thought it would be fitting to discuss some of the first female ophthalmologists in our field.

            Although female physicians began to receive training following the graduation of Elizabeth Blackwell from Geneva Medical College in 1849 and the establishment of the Women’s Medical College in Philadelphia in 1850, there was still a great amount of push-back when it came to training in a surgical specialty (the AMA did not admit women until 1915). Despite these set-backs, the two first female ophthalmologists – Isabel Hayes Chapin Barrows and Elizabeth Sargent – completed their training near the end of the 19th century. Both physicians spent time learning at the University of Zurich, where women studied medicine as early as 1833 and were admitted as medical students starting in 1864, and at Howard University in the United States, which was founded on similar principles in 1867.

            Dr. Isabel Hayes Chapin Barrows was the daughter of a family doctor, and so grew up surrounded by the medical field. After she suffered through a miscarriage and her husband died of diphtheria, she decided to pursue a medical education. However, life continued to place strains on her education, which was placed on hold as took over her second husband’s stenography job when he fell ill with typhoid fever. Finally, Dr. Barrows graduated from the Women’s Medical College of the New York Infirmary for Women and Children. She then moved to Zurich and Vienna, where she fell in love with the eye and learned the art of cataract surgery with Professor Eduard Jaeger. After completing her training, Dr. Barrows returned to Washington, DC to purchase 100 dollars worth of ophthalmology equipment and to become the first woman to have a private practice in medicine in the city.

            From a young age, Dr. Elizabeth Sargent (who was the daughter of a politician father and an activist mother) was an advocate for women’s rights and worked for the women’s suffrage. Like Dr. Barrows, she also attended Howard University before obtaining her medical degree, and she also traveled to Zurich for her training in ophthalmology. When she returned to San Francisco, Dr. Sargent continued her women’s suffrage work and began a practice in pediatric ophthalmology. She became a leader both at home and around the world, donating to keep her women and children’s hospital open and even representing the AMA’s Section on Ophthalmology at an international meeting.

”News” from The Ophthalmic Record: A Monthly Review of the Progress of Ophthalmology, Volume 9

            Together, Drs. Barrows and Sargent helped to pave the way for future female ophthalmologists, and future female physicians in general. Although there is always progress to be made, these first steps were important and these physicians deserve particular recognition today. For more information about Drs. Barrows and Sargent, you may like to read this AAO article (LINK) by Alice R. McPherson and Daniel M. Albert, on which this text is based. We hope that you enjoyed today’s reading!

            -Michael Venincasa

In last week’s episode, Jay was joined by Dr. Yoshi Yonekawa and Dr. Will Parke for Journal Club. The three publications discussed involved pediatric retinal detachment surgery, open label extension of RISE and RIDE, and blood pressure fluctuations during intravitreal injections. 

One of the articles discussed during Journal Club centered around the treatment for diabetic retinopathy. Diabetes is one of the most common chronic diseases in the United States, with the CDC estimating that more than 100 million people in the US have either diabetes or prediabetes. Currently, it is expected that 2 out of 5 Americans will develop type 2 diabetes in their lifetime. This disease carries the risk of many complications, including vision loss, neuropathy, nephropathy, skin problems and more. Importantly, it is the leading cause of vision loss in patients between 25 and 74 years of age. Because of the great global burden of diabetes and its impact on vision loss, in this post we wanted to review the classifications of diabetic retinopathy, and how the use of a monoclonal antibody can aid in treatment of this condition.  

Diabetic retinopathy is the most common microvascular complication of diabetes and it is classified into either nonproliferative or proliferative subtypes. Nonproliferative DR represents the first visible changes seen in the retina due to diabetes. In this stage microaneurysms begin to appear as well as dot intraretinal hemorrhages, and retinal ischemia or infarction represented by “cotton wool” spots. Proliferative DR represents the end stage in the natural history of DR and presents with angiogenesis, or the formation of new blood vessels. In this stage there is severe hypoxia that stimulates the production of angiogenic factors, including VEGF. 

(Left) Image Credit: https://www.researchgate.net/figure/Moderate-non-proliferative-diabetic-retinopathy-with-no-diabetic-macular-edema_fig2_310612920

(Right) Image Credit: http://retinavitreous.com/diseases/dm_pdr.php

The RIDE and RISE Studies are long-term clinical studies looking at the use of Ranibizumab, a monoclonal antibody fragment, to treat proliferative diabetic retinopathy. This monoclonal antibody is designed to inhibit VEGF and prevent angiogenesis. VEGF, or Vascular Endothelial Growth Factor, is a protein produced by cells that stimulates the formation of blood vessels and endothelial cell growth, and causes the breakdown of the blood-retinal barrier. The state of severe hypoxia seen in proliferative DR induces the production of this molecule, which leads to retinal neovascularization. These new blood vessels are fragile, prone to bleeding, and can grow into the vitreous body. Thus, sight-affecting complications include vitreous hemorrhage and tractional retinal detachment. Monoclonal antibodies like Ranibizumab have been developed to prevent this progression by inhibiting VEGF. 

An antibody molecule consists of four different polypeptide chains that join together to form a “Y” shape. Each antibody consists of two identical heavy chains and two identical light chains. Both polypeptides have a constant region and a variable region, and it is this variable region that binds to an antigen. A monoclonal antibody fragment, like the one used in the RIDE and RISE studies, only contains the antigen-binding fragment (Fab region) which is composed of both a heavy and a light chain with constant and variable regions. The loss of the Fc region makes this monoclonal antibody smaller allowing it to penetrate the retina more easily. Once in the retina, this antibody can bind to and inhibit VEGF, which prevents the molecule from binding to its receptor and thus helps to limit the progression of proliferative DR. 

-Amy Kloosterboer

(Left) Image Credit: https://bxcell.com/antibody-structure/

(Right) Image Credit: https://www.scoop.it/t/victrelis-boceprevir-merck-fda-review-approval/p/4069081506/2016/09/13/scfv-fab-construction-and-purification-fab-creative-biolabs