Tag: CRISPR

Let’s Chat About … CRISPR and Gene Editing

For the first time, early research data shows that a gene editing technique called CRISPR improved vision in people living with a form of Leber congenital amaurosis (LCA), according to Dr. Edmond Chen of Editas Medicine.

“It’s the first time anyone has demonstrated the potential of editing in human eyes,” Dr. Chen said. “We kind of dreamed about this since 2014.”

Researchers administered EDIT-101, an experimental CRISPR gene editing medicine, through a subretinal injection to reach and deliver the gene-editing machinery directly to the retina’s photoreceptor cells.

The research targets LCA10 caused by a mutation in the CEP290 gene, the most common of the more than 27 forms of LCA. 

Dr. Edmond Chen headshot
Dr. Edmond Chen

Dr. Chen is the Vice President of Clinical Development at Editas Medicine, a gene editing company based in Cambridge, Mass. The company focuses on developing CRISPR-based treatments. 

CRISPR (pronounced “crisper”) is an acronym for Clustered, Regularly Interspaced, Short Palindromic Repeats. It refers to a recently developed gene editing technology that can revise, remove, and replace DNA in a highly targeted manner.

As part of our Hope in Focus webinar series, Dr. Chen described the early, but exciting, data from the ongoing Phase 1/2 Brilliance clinical trial of EDIT-101 in our October episode: “Let’s Chat About…CRISPR and gene-editing technology.”  Our Director of Marketing and Communications Elissa Bass moderated the session, which you can view here.

Dr. Chen oversees a portfolio spanning the therapeutic areas of hematology, oncology, ophthalmology, and neuroscience. As a physician executive with more than 20 years of combined clinical and industry experience, he has a track record of success at companies, including Merck and Bayer. 

His therapeutic area and drug development expertise is deep and diverse, from rare disease and indications such as bronchiectasis, vasculitis, and pulmonary hypertension, to large cardiovascular areas including congestive heart failure, thrombosis, and therapeutics for primary and secondary cardiovascular prevention. 

He earned his medical degree at the University of California, San Francisco School of Medicine, where he trained and practiced in internal medicine and cardiology. He holds a Bachelor of Arts with Honors in Molecular and Cell Biology, Neurobiology, from the University of California, Berkeley. 

Exciting early results for CRISPR 

Dr. Chen described his passion for innovation and his interest in developing life-saving treatments, including a new aspirin.

Then he thought to himself, “We probably don’t need another aspirin,” and pivoted this passion for innovation to life-altering research, including working with the CRISPR gene-editing treatment.

He has been with Editas since 2020; the company’s work on LCA10 began in 2014. 

Dr. Chen said he is excited about the first results of the clinical trial and added that the research is part of an ongoing, current investigation of which “we’re not making any claims.”

Editas recently released early results of the first six patients in the EDIT-101 Brilliance trial at the International Symposium on Retinal Degeneration. Efficacy results were limited to the first five patients treated with the low- to mid-doses and followed for at least three months. 

Two of the three patients treated with the mid-dose and followed for up to six months showed improved vision, results that suggest successful editing with EDIT-101. Patients will need to be treated and followed over time to ensure the safety and efficacy of the drug. EDIT-101 is now being assessed at a higher dose and in pediatric patients.

Editas currently is recruiting for children, ages 3 to 17. For recruitment information, contact Editas Medicine’s Clinical Trial Team at 617-401-9007 or patients@editasmed.com. For more information, go to clinicaltrials.gov NCT03872479.

CRISPR is a one-time treatment

Explaining the gene-editing process, Dr. Chen shared some biology basics on DNA, RNA, and proteins, and described the potential of CRISPR gene-editing to restore cellular function. 

He described DNA as the building blocks of life, serving as a blueprint, or instructions, for all the proteins in our bodies. When the body reads the DNA, it makes RNA, which then acts like a messenger taking the instructions all over the body to make proteins. Proteins are the tools our cells need to function.

Sometimes, an abnormal change in DNA’s sequence (a mutation) causes disease. These changes can be spontaneous or can be inherited from parents. This is where CRISPR-based medicines come in. Gene editing technology may be able to treat some genetic diseases by intervening at the DNA level.

To demonstrate this process, Dr. Chen, using simple colored Lego® pieces to represent DNA and RNA, explained how CRISPR gene editing medicines contain a nuclease, or a protein that edits DNA, and a guide RNA that can go in and find a specific portion of the gene and make an edit to correct the gene abnormality. 

People living with LCA10 have a disease-causing mutation in the CEP290 gene. For EDIT-101, scientists created a specific guide RNA to find the CEP290 gene in the photoreceptor cells and remove the incorrect instructions contained in the patient’s DNA.

The drug is injected one time in one eye under the retina, creating a blister-like pocket of the drug called a bleb for EDIT-101 to treat the target area that allows retina function. Dr. Chen characterized the treatment as an effective and precise process.

“The DNA is actually edited with the genetic defect corrected,” he said. “It’s a very elegant use of science for which the Nobel Prize was given, so this is a big deal.”

Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the 2020 Nobel Prize in chemistry for their 2012 discovery of CRISPR.

Still a few years to market

One of our webinar viewers asked why the process can’t be used to treat all other forms of LCA.

“It’s a long road,” Dr. Chen said. “For good reasons, the regulatory path is a long one.”

The process can take 15 to 20 years, from molecular research to studying treatment effects in animals and then humans, to undergoing the rigors of earning approval by the U.S. Food and Drug Administration.

In 2017, the FDA approved LUXTURNA,® the first, and so far, only, gene therapy for a form of LCA. Gene therapy is different than gene editing. Gene therapy entails inserting a “healthy” version of the gene to offset the effect of the mutation, while gene editing revises, removes, or replaces a mutated gene at the DNA level.

This study of EDIT-101 centers on one form of LCA and it is in its initial stages, he said.

“Each of the defects, you could add it up and it’s a long, expensive and laborious exercise. It’s a commitment on our part. None of this is easy.”

He estimated that getting the CRISPR treatment to market is still a few years away.

In answer to a question about what keeps him going amid the arduous trial-and-error process that comes with clinical research, he said, some days are very frustrating, but he feels blessed to make a difference in someone’s life.

“It’s all about the patient,” Dr. Chen said. “That makes a world of difference and makes it all worthwhile.”

‘Let’s Chat About …’ Webinar Offers LCA Overview and Updates on Clinical Trials

In the debut of Hope in Focus (formally Sofia Sees Hope) ‘Let’s Chat About …’ monthly webinar series, Ben Shaberman of the Foundation Fighting Blindness, provided his Zoom audience with a plethora of information about Leber congenital amaurosis (LCA), highlighting some of the more than 40 clinical trials underway to find treatments and cures for LCA and other rare inherited retinal diseases (IRDs) and giving updates on promising preclinical research. 

The recorded webinar aired 1 p.m. Wednesday, Jan. 27, 2021, and can be seen here. Elissa Bass, our marketing and communications director, moderated the session.

Shaberman, Senior Director, Scientific Outreach & Community Engagement, stumbled across a science writing position at the Foundation Fighting Blindness 16 years ago without a clue about retinas or blindness. He called his move to the Foundation serendipitous. He knew he made the right choice after hearing retinal researcher Dean Bok, PhD, tell attendees at a 2005 Foundation conference how he was drawn to the field by the seduction of the retina’s myriad complexities and inner workings.

Shaberman, too, felt pulled by the intriguing science of the retina.

As such, so are the 27 forms of LCA that cause varying kinds of visual impairment within each gene mutation and within each affected person. An estimated 8,000 people in the United States have LCA.

The path of retinal research

Shaberman took his audience from the beginnings of identifying the RPE65 gene in 1993 and learning shortly thereafter it could lead to LCA, to using mice models and later studying Briard dogs that had the same gene mutation that caused LCA in humans. A clinical trial at Children’s Hospital of Philadelphia led to the 2017 FDA approval of the breakthrough gene therapy LUXTURNA®, developed by Spark Therapeutics. The drug successfully improved the vision of many of the LCA2-RPE65 patients who received the treatment through subretinal injections.

When children receive an LCA diagnosis, their families should find a good retinal specialist, get regular exams, and ultimately get a confirmed genetic diagnosis to be on the path to more specific information and research into that form of LCA, Shaberman said.

Families also should register with the Foundation’s My Retina Tracker®, a free and secure online registry that facilitates getting a confirmed genetic diagnosis by making registrants eligible for free genetic testing.

The registry becomes your personal retinal health record, updated by you. It employs state-of-the-art database technology to protect privacy and adheres to the highest standards of confidentiality and ethics. 

It also notifies registrants of clinical trials and gives researchers access to their disease data – not their personal information – to advance research and therapy development associated with LCA and IRDs. 

Reading research publications and attending events sponsored by the Foundation and by Sofia Sees Hope also provide opportunities for families to interact and learn the latest research. Shaberman and Bass encouraged people affected by LCA and their families to contact them, respectively, through the Foundation’s website and/or the Sofia Sees Hope website for specific information on clinical trials or other questions and concerns about living with LCA. 

“Yes, it’s work,” Shaberman said. “You have to be your own advocate and your own child’s advocate, but more and more information is becoming available, and that’s the good news.”

More than 40 clinical trials underway

Shaberman also reviewed some of the more than 40 retinal clinical trials in the pipeline for LCA and other IRDs:

Join us Feb. 16

February’s “Lets Chat About …” webinar airs at 3 p.m. ET, Tuesday, Feb. 16. Our guest will be Wiley A. Chambers, MD, Supervisory Medical Officer for the Office of New Drugs, Center for Drug Evaluation and Research at the U.S. Food and Drug Administration. Register here.

Retinal Disease Gene Therapy Breakthroughs Trace Their Roots to 19th Century Research

Theodor Karl Gustav von Leber would be proud. So would Adolphe Franceschetti and Carl-Henry Alström. 

Their research from the 19th and 20th centuries laid the foundation for groundbreaking gene therapy to treat Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs). Translational research focused on LCA helped bring forth unprecedented numbers of genetic clinical trials now underway for IRD treatments and cures.

Dr. Tomas S. Aleman, associate professor of ophthalmology and director of the Hereditary Retinal Degeneration Clinics at the Perelman Center for Advanced Medicine and the Center for Advanced Retinal and Ocular Therapeutics at the University of Pennsylvania, discussed the beginnings of research into retinal degeneration as part of his presentation at the Hope in Focus (formally Sofia Sees Hope) second LCA Family Conference in Philadelphia last summer.

Dr. Aleman joined three panelists in a conference session called “One Disease, Many Approaches,” moderated by Brian Mansfield, PhD, executive vice president of research and interim chief scientific officer for the Foundation Fighting Blindness. 

In a research paper published in 1871, Dr. Theodor Karl Gustav von Leber recognized early-infancy severe retinal disease with pupils that are “amaurotic,” related to amaurosis, meaning dimming, darkening, dark or obscure. Amaurotic pupils do not relate to light normally, expanding and contracting more slowly than normal or not responding to light at all. A large group of early-onset inherited retinopathies causing blindness carry his name as Leber’s Congenital Amaurosis. 

“His descriptions still endure,” Dr. Aleman told his audience of more than 80 people from across the country and Mexico.

The evolution of research

Dr. Tomas S. Aleman, associate professor of ophthalmology and director of the Hereditary Retinal Degeneration Clinics at the Perelman Center for Advanced Medicine and the Center for Advanced Retinal and Ocular Therapeutics at the University of Pennsylvania

Dr. Adolphe Franceschetti authored more than 500 articles throughout his life (1896-1968), realizing the retinal origin of the blindness and working on ocular genetics, Dr. Aleman said. A specific behavior comprised of poking, pressing and rubbing the eyes with a knuckle or finger to mechanically evoke perception of light is called Franceschetti’s oculo-digital sign and is characteristic of LCA. Researchers suspect this behavior in affected children may contribute to deep-set eyes and keratoconus, a condition in which the normally round cornea thins and bulges into a cone-like shape, causing distorted vision.

Dr. Carl-Henry Alström confirmed that LCA is genetic in nature, and he is credited with recognizing in the 1950s syndromic forms of LCA and other early-onset retinopathies such as Bardet-Biedl Syndrome, a rare genetic disorder with highly variable symptoms that may include retinal degeneration, obesity, reduced kidney function and many other features.

LCA occurs in 1 in 30,000 to 1 in 80,000 people and makes up 5 percent of all retinal dystrophies. Twenty percent of children with visual impairment and attending special schools have LCA.  

LCA, thought of as one disease until 40 years ago, now consists of more than 27 forms.

“It’s a large pack of diseases,” Dr. Aleman said.

Decades of work toward success

He characterized LCA as a molecularly heterogenous or diverse group of diseases with most primary disease location within the cells that perceive light or photoreceptors. Dr. Aleman detailed the complexities of clinical exams, vision testing and the spectrum of severity of vision loss observed in LCA. One such scenario, known as structural-functional dissociation, occurs when the loss of vision is disproportional to the loss of photoreceptors and is frequently seen in LCA, particularly very early in life. Such scenario represents the ideal for gene corrective treatment strategies. 

RPE65-LCA studies led by a group of researchers at the University of Pennsylvania dating back to the late 1990s solidly demonstrated LCA could be treated. Dr. Aleman  cited the importance of the translational research and clinical trials that led to federal approval of LUXTURNA™, a gene therapy treatment for LCA2 or RPE65-LCA, saying other, more frequent and neglected diseases have gotten attention through the RPE65 story.

He singled out two researchers, Jean Bennett, MD, PhD, who joined him on the conference panel, and her partner in research and marriage, Dr. Albert M. Maguire. He pointed out that their foresight and drive pushed research beyond the initial gratification granted by the spectacular results of early multi-institutional RPE65 gene therapy trials, to fulfill the practical need of an approved treatment for use in the clinic. The treatment, which produces dramatic gains in visual sensitivity, is the first and is, to date, the only gene therapy product approved for clinical use for an inherited retinal disease in the United States and Europe.

More patients have been treated with LUXTURNA since its approval in December 2017 by the U.S. Food and Drug Administration than those who received the medication during the clinical trials.

“I like to think that if it wasn’t for Jean and Albert, we wouldn’t be where we are today,” he told the gathering of patients, patient advocates, family members, researchers, doctors and biotechnology leaders.

No cure yet; work continues

Having one retinal gene therapy approved for use in the clinic, 900 patients enrolled in trials across 30 sites, and progress on therapies for the most severe forms of LCA, Dr. Aleman said, “That should stimulate ourselves to continue.”

He noted that much work remains to be done: LCA has not been cured, and researchers do not have a solution for every type of LCA. Gene therapy may not be enough for every patient or form of LCA, and the potential outcomes after treatments should not be expected to be the same across the heterogeneous group of diseases under the LCA umbrella.

In closing his presentation, Dr. Aleman posed three questions regarding LCA treatment and research: 

  • Can we treat hereditary retinal degenerations/LCA? “Yes, the answer is yes.
  • Can we defeat LCA? “And the answer is also yes.” 
  • Do we have the tools and people to do it? “The answer is also yes.”

Dogs as test cases

In her presentation, Dr. Jean Bennett described how the RPE65 gene, when mutated, causes LCA2 or RPE65-LCA. In early research, Briard herding dogs that carried the mutated gene gained improved vision after receiving subretinal injections of an engineered virus of the human RPE65 gene. The treatment works by encoding an enzyme that converts light into electrical signals interpreted by the brain.

Dr. Bennett was one of the first investigators to use viral vectors, in which a virus is used as a vector or carrier that is genetically engineered to deliver the gene to specific cells in the retina. She is professor of ophthalmology at the Center for Advanced Retinal and Ocular Therapeutics and the F.M. Kirby Center for Molecular Ophthalmology at the Perelman School of Medicine. Please see a related story detailing her conference presentation. 

Pam Stetkiewicz, PhD, vice president of program management at Editas Medicine, described a different approach using gene editing technology developed by Editas. The treatment uses molecular biology to create genomic medicine that precisely edits – by locating and removing – the targeted mutation in LCA10 or CEP290-LCA. She said the technology builds on the foundation inspired by Dr. Bennett’s gene replacement therapy.

More treatments in the works
Pam Stetkiewicz, PhD, vice president of program management at Editas Medicine

Editas Medicine, based in Cambridge, Mass., in partnership with Allergan, based in Dublin, Ireland, use CRISPR/Cas9 gene-editing technology to accomplish DNA editing. The treatment, called EDIT-101, cuts out the mutation and is delivered to photoreceptors by subretinal injection. The editing permanently corrects the original, non-functioning protein essential for vision.

Dr. Stetkiewicz said Editas hopes to use the medicine to treat LCA10. Additionally, the company is developing experimental medicines to treat Usher Syndrome 2A and Retinitis Pigmentosa, among other IRDs. Editas is also working to develop engineered cell medicines to treat cancers and blood diseases, including Sickle Cell Disease. 

The FDA approved the company’s 10,000-page data package, securing the required Investigational New Drug (IND) application to begin clinical studies with EDIT-101 in humans.

Editas and Allergan currently are recruiting patients with CEP290-LCA for a natural history study that will create the basis to test safety and efficacy in the Phase 1/2 clinical trial of EDIT-101.

Dr. Stetkiewicz said preclinical data shows that EDIT-101 is well-tolerated, efficacious and safe. Measurement of editing intended DNA versus unintended DNA is called specificity. Human retinal explants, pieces of tissue cultured for growth, treated with EDIT-101 resulted in a high level of intended editing with zero unintended editing, meaning the treatment has an excellent genomic specificity profile.

“So, we’re thrilled with this result,” she said. 

Phase 1/2 clinical trials will begin in the second half of this year with 18 patients age 3 years and older at clinical sites in Massachusetts, Florida, Oregon and Michigan.

DNA, RNA, & LCA
Michael Schwartz, M.S., MBA, is vice president of ophthalmology at ProQR Therapeutics and is the global project leader for Sepofarsen (QR-110), an RNA therapy under development.

Panelist Michael Schwartz, M.S., MBA, is vice president of ophthalmology at ProQR Therapeutics and is the global project leader for Sepofarsen (QR-110), an RNA therapy under development. 

ProQR, based in The Netherlands with offices in Cambridge, Mass., is developing an antisense oligonucleotide (AON) product, Sepofarsen (QR-110), designed as a disease-modifying therapy for LCA due to the c.2991 +1655A>G mutation (p.Cys998X) in the CEP290 gene. The company is developing AON products, which are RNA therapies primarily for ophthalmic inherited disease. AON are short, single-stranded RNA molecules that interact with messenger RNA to prevent translation of a targeted gene.

Sepofarsen works like genetic tape to block the mutation p.Cys998X in the CEP290 gene.

To help understand what this means, Schwartz presented background on DNA, RNA and LCA:

The body comprises many different cells, and we have DNA in each of these cells. DNA contains many instructions for making all the different proteins, which are important building blocks needed by a cell.

When the cell needs a building block, it first copies instructions to a shorter blueprint called RNA; the RNA is then used to guide how to make a new protein, like CEP290. Together, these different proteins make sure the cell works as it should, resulting in normal vision.

But things don’t always go right. Inherited diseases are caused by mistakes in the DNA, and then these mistakes are copied into the RNA, as in the p.Cys998X mutation in CEP290.

This means that the proteins also will have the mistakes in them. They can’t work properly, and the cell cannot function as it should. This is what causes LCA.

He also detailed the workings of RNA therapies, saying they consist of short RNA molecules, with the aim to repair the mutation in a patient’s RNA – without changing the DNA – and to restore the function of the protein and the cell to hopefully improve vision.

A normal CEP290 protein maintains cilium structure in the photoreceptors of the retina and enables normal protein transport to the photoreceptor outer segment.

The CEP290 p.Cys998X mutation creates an environment that results in an aberrant exon that disrupts the splicing code of genes by truncating the CEP290 protein, ultimately leading to the degeneration of the photoreceptor cells.

Sepofarsen, delivered by intravitreal injection, blocks the recognition of the aberrance, and that results in favoring production of normal protein. 

“We can actually reverse the phenotype of that mutation,” Schwartz said.

ProQR is finalizing interim results of its ongoing Phase 1/2 trial involving 11 people from ages 8 to 44. Schwartz said most of the patients had clinically meaningful improvement. The company’s Phase 2/3 trial began, with the first patient dosed in April. The 24-month trial expects to enroll 30 patients.

He cited an exceptional patient responder in the Phase 1/2 trial in which an adult with only light perception vision before the trial could now read letters on the eye chart.

“They said they could see things out of the treated eye that they had not seen for decades.”

The Road to Treatment: Understanding How Therapies Are Developed

Successful clinical drug trials are a cornerstone of U.S. Food and Drug Administration approval, such as with LUXTURNA™, a ground-breaking genetic therapy that helps restore vision in Leber congenital amaurosis (LCA) patients with a mutation in their RPE65 gene (LCA2).

But the FDA’s Dr. Wiley A. Chambers II cautioned LCA families and patients at a recent LCA Family Conference hosted by Hope in Focus (formally Sofia Sees Hope) to make sure their clinical trial of interest is real and not bogus.

Clinical trials drive research with the goal of finding treatments or cures that need FDA approval before commercial use. Twenty-three gene-based clinical trials targeting 13 genes are underway, including an LCA4 (AIPL1) trial, according to Foundation Fighting Blindness. More than 20 retinal cell therapy trials are in progress, and another 100 genes are under investigation in the preclinical pipeline, the Foundation reported.

Dr. Wiley Chambers II, MD headshot
Dr. Wiley Chambers II, MD

Chambers is supervisory medical officer in the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research. The center’s mission is to assure that safe and effective drugs are available to the American people.

He was among three panelists who joined moderator Jeffrey Finman, PhD., of Jupiter Point Pharma Consulting, in exploring the development and approval of new treatments for rare diseases, including LCA. The panel was part of Sofia Sees Hope’s first-ever LCA Family Conference in Groton, CT, on Oct. 6.

Jennifer Hunt with Editas Medicine, a discovery-phase biotechnology company, and Tami Morehouse, a participant in the breakthrough LCA2 (RPE65) genetic therapy trial joined Chambers on the panel.

Not all trials are ‘real’

“Be aware of any trial where you’re charged for the drug or biologic product,” Chambers said. “If they’re charging you, watch out.”

He said every clinical trial is assigned an Investigational New Drug (IND) number. No number, no real trial.

Chambers sited the disastrous case of a 77-year-old woman who traveled to Georgia to have stem cells injected in her eyes in the hopes of a cure or at least help for her macular degeneration. The procedure entailed taking fat from the woman’s belly, separating stem cells that naturally occur in fat, and injecting them into her eyes to regenerate damaged tissue.

The procedure, not covered by insurance and not approved by the FDA, cost the woman $8,900. Within three months, her retinas – the eye’s layer of light-sensitive cells – had peeled away from the rest of her eyes. Her vision deteriorated to where she only could see hand movement before her eyes. She no longer could find her way on her own.

Risks vs. benefits

To fulfill its mission, the FDA monitors the drug development process during investigational stages, approves new drug products that are safe and efficacious, and monitors post-approval adverse events.

The FDA does not conduct clinical studies, choose which products a company will study, force companies to market products, or regulate the practice of medicine.

Approval depends on whether the benefits of a drug outweigh the risks.

“There is always a risk,” Chambers said. “If it does anything positive, it does something negative…It’s a balancing act.”

The factors weighed in this balancing act of forces and interests, clinically referred to as equipoise, consist of:

  • the potential benefit from the drug product;
  • the potential adverse event from drug;
  • the potential safety from not taking a new drug;
  • the potential loss from disease condition if not taking an effect therapy;
  • and missing out on an alternative therapy.

Exploring different routes to a cure

Panelist Jennifer Hunt, vice president of clinical operations for Editas Medicine, described the process of developing a medicine that corrects mutated genes through editing. Using her company’s investigational medicine, EDIT-101, as an example, she detailed the course for finding an ocular medicine to treat patients with LCA10 (CEP290). LCA10  is one of the leading causes of blindness beginning in the first years of life.

Editas is working on developing CRISPR-based medicines (pronounced crisper, and meaning Clustered Regularly Interspaced Short Palindromic Repeats). CRISPRs are specialized stretches of DNA; the protein Cas9, meaning CRISPR-associated, is an enzyme that acts like a pair of molecular scissors, capable of cutting strands of DNA, according to LiveScience. 

EDIT-101 is poised to be the first in vivo CRISPR medicine used in human trials. Before those clinical trials begin, researchers have been looking to answer key questions, such as, does editing restore protein expression in cells and what are the best clinical trials for patients?

Editas researchers also are conducting an ongoing natural history study with 40 patients, ages 3 and older. They are followed up with six times over the course of a year at seven sites – four in the United States and three in Europe – to characterize them, assess their vision changes and validate study endpoints.

Editas has stated it plans to file an Investigational New Drug (IND) application with the FDA in October. Once allowed by the FDA, Editas can begin clinical trials.

The FDA evaluates three study phases of a proposed new drug:

  • Phase 1 investigation of new drugs in humans is a phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to determine the drug’s most frequent and serious adverse events and, often, how the drug is broken down and excreted by the body. These trials usually involve a small number of participants.
  • Phase 2 consists of research to describe clinical trials that gather preliminary data on whether the drug is effective in people who have a certain condition/disease. Participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance, called a placebo, or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.
  • Phase 3 research is to describe trials that gather more information about a drug’s safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.

The human side of a drug trial

The third panelist, Tami Morehouse, spoke to the safety and effectiveness of LUXTURNA, a medication developed by Spark Therapeutics that the FDA approved last December for commercial use. Tami made medical history at age 44 when she became the oldest person to participate in the successful Phase 1 LCA-RPE65 genetic therapy clinical trial in 2009.

Dr. Jean Bennett and her husband, Dr. Albert Maguire successfully used the treatment on Lancelot, a dog born blind with a mutation in his RPE65 gene, before testing the medication on humans.

Prior to the trial, Tami could see faces, but much of the time she saw dark, gray haze. She woke up every morning when her alarm clock went off, wondering, would this be the day she would wake up with no vision.

“I had no hope whatsoever,” she said.

Her husband, Michael, added, “That’s where she’d be today were it not for that trial.”

Michael learned of Dr. Bennett and her ongoing clinical trials at Children’s Hospital of Philadelphia (CHOP) from a radio broadcast.

The trials resulted in FDA approval of LUXTURNA, a gene therapy that enabled Tami to regain some of her vision.

“It was an incredible experience that was a long time coming,” she said.

Tami said she is “walking, living proof” of the treatment’s safety and effectiveness. She told her audience to keep in mind that older people, along with children and young adults, can benefit from the treatment.

“Don’t give up hope and keep looking.”

IRD Milestones: Reasons to Be Excited

1971 – Just those numbers in white on a black page appeared on the big screen.

That’s how Brian Mansfield, PhD., began his presentation to families and patients living with Leber congenital amaurosis at Hope in Focus (formally Sofia Sees Hope) LCA Family Conference on Saturday, Oct. 6, in Groton, CT.

The year on that otherwise empty page marked the founding of Foundation Fighting Blindness – a time when patients losing vision often heard, “Go home. Learn Braille. You are going to go blind.”

Mansfield’s audience at the conference was made up of people diagnosed with a variety of rare inherited retinal diseases, including LCA, their caregivers and relatives, and representatives of various bio-tech and pharmaceutical companies working in the IRD arena. It was Sofia Sees Hope’s first such conference.

Dr. Brian Mansfield headshot
Dr. Brian Mansfield

Mansfield is the foundation’s senior vice president of research. He brought his audience up to date with information about clinical trials for inherited retinal diseases (IRDs), the rich preclinical therapeutic pipeline, how the Foundation uses money to move treatments forward and what people can do to drive change for IRD treatments and therapies.

His presentation culminated in a projected slide filled with logos of bio-technology and pharmaceutical firms, many of which are in contact with the Foundation, and represent the ever-expanding research and development field to help people with visual impairment.

$725 million in funding

In its 47 years, Foundation Fighting Blindness has raised more than $725 million toward research, development and public health education. It partners with several dozen U.S. non-profit organizations, including Sofia Sees Hope.

Mansfield traced the rapid trajectory of identifying genes causing retinal disease, from the founding of the National Eye Institute in 1968 through the Foundation’s funding of the Berman-Gund Laboratory for the Study of Retina Degenerations in 1971. It included the 1989-90 work identifying the rhodopsin gene as the genetic cause of Retina Pigmentosa (RP), and conducting the first retinal disease gene therapy trials in 2007. And of course culminated in last December’s federal approval LUXTURNA™, a gene therapy that helps restore vision in people with LCA2 (RPE65).

For people affected by LCA, more than 80 percent can now get a clear genetic diagnosis. For IRDs, more than 260 retinal disease genes have been identified, and the overall success in providing a clear genetic diagnosis is 65 percent.

Mansfield said that 23 gene-based clinical trials targeting 13 different genes are currently underway, including the LCA4 (AIPL1) gene trial by MeiraGTx.

A promising pipeline

He said the gene therapy preclinical pipeline is promising, with 100 genes under investigation. Researchers also are conducting preclinical studies of optogenetic gene therapies, in which light is used to control genetically modified retinal cells.

ProQR is planning a pivotal Phase 2/3 gene patch clinical trial for the LCA10 (CEP290) gene that involves injecting a short DNA molecule to cover up the faulty instruction the gene otherwise gives to act incorrectly. Also, Mansfield said, Editas Medicine is close to gene editing clinical trials, called “cut and paste” because an enzyme seeks out and repairs the defective gene. Another editing therapy in the pipeline, called base editing, essentially backspaces over the mutation and types the correction over it.

Also underway are more than 20 retinal cell therapy trials in which lost cells are put back to replace missing cells or used as biofactories to produce factors that help stabilize the retinal cells.

To help propel research and trials, the Foundation funds Career Development Awards to attract and retain clinician researchers dedicated to retinal disease research. The Foundation also provides awards to the brightest minds in the field, individually or as a team, to drive research.

It also gave 16 years of preclinical research support amounting to $10 million toward Spark Therapeutics’ commercial gene therapy, LUXTURNA, the first directly administered gene therapy approved in the United States that targets a disease caused by mutations in a specific gene – LCA RPE65.

Mansfield talked about how Applied Genetics Technology Corp. (AGTC) leveraged an early Foundation investment to garner $265 million to develop genetic therapies, some of which are in clinical trials.

The Foundation also supports 20 centers – the International Clinical Consortium – that have standardized assessment protocols for clinical trials.

Patient involvement is key

To continue to attract industry interest, Mansfield detailed the Foundation’s My Retina Tracker registry, with its tagline “Track your vision. Drive the research.” It’s a free, secure, online patient registry that notifies registrants of clinical trials and gives researchers access to their disease data – but not their personal information – to advance studies on any number of research and therapy development efforts associated with IRDs.

The power of My Retina Tracker is optimized by registrants getting a genetic diagnosis. Sofia Sees Hope donated $65,000 to help people receive genetic testing and counseling.

Mansfield emphasized to his audience the vital importance of their knowledge, what they carry with them, and that patient input is critical to drug development.