Penn scientists correct genetic blindness with single injection into the eye

Antisense oligonucleotide therapy uses small molecules to alter RNA. Researchers have now used those molecules to alleviate a genetic form of blindness.

Credit: DDP via Unsplash

This article was originally published on our sister site, Freethink.

Researchers at the University of Pennsylvania have reversed a genetic form of blindness in a patient using just one course of antisense oligonucleotide therapy, Clinical OMICS reports.

The therapy, which takes aim at mutant RNA, was injected into the patient's eyes a year ago, in a trial treating Leber congenital amaurosis (LCA). LCA predominantly affects the retina, leaving people with severely impaired vision from birth, according to the NIH.

The trial, held at the Scheie Eye Institute at Penn's Perelman School of Medicine, focused on using antisense oligonucleotide therapy to treat LCA patients with one of the disease's most common mutations.

Augmenting RNA

Antisense oligonucleotide therapy works by altering the RNA, the messenger that carries instructions from your DNA to crank out proteins.

An article in Nature Reviews Neurology describes antisense oligonucleotides as "short, synthetic, single-strand" molecules, which can alter RNA to cause protein creation to be reduced, enhanced, or modified.

In the Penn study, the targeted protein was created by the mutated LCA gene.

The team, led by professors Artur V. Cideciyan and Samuel G. Jacobson, injected an antisense oligonucleotide (called sepofarsen) into the eyes of 11 patients.

In a previous study, according to Clinical OMICS, the team had shown that administering the therapy every three months increased the amount of the proper protein levels in 10 patient's eyes, improving their sight in daytime conditions.

But it's the experience of the eleventh patient that's the subject of their new paper, published in Nature Medicine.

One shot

That eleventh patient chose to receive only one course of sepofarsen and turned down the additional doses.

The patient had suffered from poor visual acuity, reduced fields of view, and zero night vision, Clinical OMICS reports, but after one shot, the patient showed remarkable improvement over the course of the next 15 months — similar to people who got multiple, regular injections.

"Our results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations," Cideciyan told Clinical OMICS.

Interestingly, the effects of the shot had a delayed onset; while improvement was shown after one month, the gains peaked around three months later, the authors write. That slow uptake was unexpected, and it may hold insights into treating other diseases that impact retinal cell's cilia (aka, those little vibrating hairs), the physical cause of LCA.

Antisense oligonucleotide therapy may be effective because the tiny molecules can slip inside the cell's nucleus, but don't get swept out too quickly, so they can stick around until the job's done.

The therapy's success, and the unexpected success of a single injection, is inspiring other clinical trials.

"This work represents a really exciting direction for RNA antisense therapy."
SAMUEL G. JACOBSON

"There are now, at least in the eye field, a series of clinical trials using antisense oligonucleotides for different genetic defects spawned by the success of the work in CEP290-associated LCA from Drs. Cideciyan and Jacobson," Joan O'Brien, chair of ophthalmology and director of the Scheie Eye Institute, told Clinical OMICS.

Multiple antisense therapies have already been approved by the FDA, particularly for neurological conditions, and have shown success in treating spinal muscular atrophy and Duchenne muscular dystrophy. Per Neurology Genetics, antisense oligonucleotide therapy trials are currently being developed for Huntington's, Parkinson's, and Alzheimer's disease, among others.

And now add genetic blindness to that list.

"This work represents a really exciting direction for RNA antisense therapy. It's been 30 years since there were new drugs using RNA antisense oligonucleotides," Jacobson told Clinical OMICS, "even though everybody realized that there was great promise for these treatments."

Meet Dr. Jennifer Doudna: she's leading the biotech revolution

She helped create CRISPR, a gene-editing technology that is changing the way we treat genetic diseases and even how we produce food.

Credit: Courtesy of Jennifer Doudna

This article was originally published on our sister site, Freethink.

Last year, Jennifer Doudna and Emmanuelle Charpentier became the first all-woman team to win the Nobel Prize in Chemistry for their work developing CRISPR-Cas9, the gene-editing technology. The technology was invented in 2012 — and nine years later, it's truly revolutionizing how we treat genetic diseases and even how we produce food.

CRISPR allows scientists to alter DNA by using proteins that are naturally found in bacteria. They use these proteins, called Cas9, to naturally fend off viruses, destroying the virus' DNA and cutting it out of their genes. CRISPR allows scientists to co-opt this function, redirecting the proteins toward disease-causing mutations in our DNA.

So far, gene-editing technology is showing promise in treating sickle cell disease and genetic blindness — and it could eventually be used to treat all sorts of genetic diseases, from cancer to Huntington's Disease.

The biotech revolution is just getting started — and CRISPR is leading the charge. We talked with Doudna about what we can expect from genetic engineering in the future.

This interview has been lightly edited and condensed for clarity.

Freethink: You've said that your journey to becoming a scientist had humble beginnings — in your teenage bedroom when you discovered The Double Helix by Jim Watson. Back then, there weren't a lot of women scientists — what was your breakthrough moment in realizing you could pursue this as a career?

Dr. Jennifer Doudna: There is a moment that I often think back to from high school in Hilo, Hawaii, when I first heard the word "biochemistry." A researcher from the UH Cancer Center on Oahu came and gave a talk on her work studying cancer cells.

I didn't understand much of her talk, but it still made a huge impact on me. You didn't see professional women scientists in popular culture at the time, and it really opened my eyes to new possibilities. She was very impressive.

I remember thinking right then that I wanted to do what she does, and that's what set me off on the journey that became my career in science.

Freethink: The term "CRISPR" is everywhere in the media these days but it's a really complicated tool to describe. What is the one thing that you wish people understood about CRISPR that they usually get wrong?

Dr. Jennifer Doudna: People should know that CRISPR technology has revolutionized scientific research and will make a positive difference to their lives.

Researchers are gaining incredible new understanding of the nature of disease, evolution, and are developing CRISPR-based strategies to tackle our greatest health, food, and sustainability challenges.

Freethink: You previously wrote in Wired that this year, 2021, is going to be a big year for CRISPR. What exciting new developments should we be on the lookout for?

Dr. Jennifer Doudna: Before the COVID-19 pandemic, there were multiple teams around the world, including my lab and colleagues at the Innovative Genomics Institute, working on developing CRISPR-based diagnostics.

Traits that we could select for using traditional breeding methods, that might take decades, we can now engineer precisely in a much shorter time. — DR. JENNIFER DOUDNA

When the pandemic hit, we pivoted our work to focus these tools on SARS-CoV-2. The benefit of these new diagnostics is that they're fast, cheap, can be done anywhere without the need for a lab, and they can be quickly modified to detect different pathogens. I'm excited about the future of diagnostics, and not just for pandemics.

We'll also be seeing more CRISPR applications in agriculture to help combat hunger, reduce the need for toxic pesticides and fertilizers, fight plant diseases and help crops adapt to a changing climate.

Traits that we could select for using traditional breeding methods, that might take decades, we can now engineer precisely in a much shorter time.

Freethink: Curing genetic diseases isn't a pipedream anymore, but there are still some hurdles to cross before we're able to say for certain that we can do this. What are those hurdles and how close do you think we are to crossing them?

Dr. Jennifer Doudna: There are people today, like Victoria Gray, who have been successfully treated for sickle cell disease. This is just the tip of the iceberg.

There are absolutely still many hurdles. We don't currently have ways to deliver genome-editing enzymes to all types of tissues, but delivery is a hot area of research for this very reason.

We also need to continue improving on the first wave of CRISPR therapies, as well as making them more affordable and accessible.

Freethink: Another big challenge is making this technology widely available to everyone and not just the really wealthy. You've previously said that this challenge starts with the scientists.

Dr. Jennifer Doudna: A sickle cell disease cure that is 100 percent effective but can't be accessed by most of the people in need is not really a full cure.

This is one of the insights that led me to found the Innovative Genomics Institute back in 2014. It's not enough to develop a therapy, prove that it works, and move on. You have to develop a therapy that actually meets the real-world need.

Too often, scientists don't fully incorporate issues of equity and accessibility into their research, and the incentives of the pharmaceutical industry tend to run in the opposite direction. If the world needs affordable therapy, you have to work toward that goal from the beginning.

Freethink: You've expressed some concern about the ethics of using CRISPR. Do you think there is a meaningful difference between enhancing human abilities — for example, using gene therapy to become stronger or more intelligent — versus correcting deficiencies, like Type 1 diabetes or Huntington's?

Dr. Jennifer Doudna: There is a meaningful distinction between enhancement and treatment, but that doesn't mean that the line is always clear. It isn't.

There's always a gray area when it comes to complex ethical issues like this, and our thinking on this is undoubtedly going to evolve over time.

What we need is to find an appropriate balance between preventing misuse and promoting beneficial innovation.

Freethink: What if it turns out that being physically stronger helps you live a longer life — if that's the case, are there some ways of improving health that we should simply rule out?

Dr. Jennifer Doudna: The concept of improving the "healthspan" of individuals is an area of considerable interest. Eliminating neurodegenerative disease will not only massively reduce suffering around the world, but it will also meaningfully increase the healthy years for millions of individuals.

There is a meaningful distinction between enhancement and treatment, but that doesn't mean that the line is always clear. It isn't. — DR. JENNIFER DOUDNA

There will also be knock-on effects, such as increased economic output, but also increased impact on the planet.

When you think about increasing lifespans just so certain people can live longer, then not only do those knock-on effects become more central, you also have to ask who is benefiting and who isn't? Is it possible to develop this technology so the benefits are shared equitably? Is it environmentally sustainable to go down this road?

Freethink: Where do you see it going from here?

Dr. Jennifer Doudna: The bio revolution will allow us to create breakthroughs in treating not just a few but whole classes of previously unaddressed genetic diseases.

We're also likely to see genome editing play a role not just in climate adaptation, but in climate change solutions as well. There will be challenges along the way both expected and unexpected, but also great leaps in progress and benefits that will move society forward. It's an exciting time to be a scientist.

Freethink: If you had to guess, what is the first disease you think we are most likely to cure, in the real world, with CRISPR?

Dr. Jennifer Doudna: Because of the progress that has already been made, sickle cell disease and beta-thalassemia are likely to be the first diseases with a CRISPR cure, but we're closely following the developments of other CRISPR clinical trials for types of cancer, a form of congenital blindness, chronic infection, and some rare genetic disorders.

The pace of clinical trials is picking up, and the list will be longer next year.

What If Algorithms Helped People, Not Corporations?

Here's one use for all that harvested personal data that you might not object to. Algorithms and big data are no longer just for profit; they can bring us self-awareness and growth.

Who knows more about you than anyone else? Perhaps it’s not so much who, but what. Our intimacy with our devices has surpassed our closeness with most of our friends and family, says Nichol Bradford, and an algorithm never forgets – it will remember everything you ever typed into a search box, how you voted, when you were sick, where your scroll slowed down on a page, how quickly you clicked a picture that it mathematically knew you would like. Until now, big data like this has been used purely for profit, so that media companies can sell advertising, and e-commerce sites can move units. But that’s about to change, explains Bradford. There is tech emerging that can not only track your external behavior, wishes and desires, but read your inner biological signals and interpret micro-expressions on your face to accurately assess your psychological state. If you put this technology into the hands of individuals, not just companies, it could help us manage our habits. This technology could first show us who we really are – objectively, with none of our ego-protective denial or projection – then be a tool to change our behavior and thinking patterns for the better. Nichol Bradford is the author of The Sisterhood.

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Will Human Skin Revolutionize Batteries?

Melanin, the pigment-producing part of human skin, may change the way batteries are manufactured and used.

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Research by Professor Christopher Bettinger of Carnegie Mellon University and his colleagues reveals that parts of human skin might be crucial to rethinking the manufacture of batteries. Specifically, melanin, the molecule that provides pigment to skin, has been shown to have helpful ion-controlling properties. The complex compound made up of carbon, oxygen, and nitrogen might be an unintuitive solution for creating batteries safe for use in human bodies, which is one of Bettinger’s goals.

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