The Future of Gene-Editing Treatments for Rare Diseases

Angelman syndrome is a rare genetic disorder caused by a mutation on chromosome 15, which hinders the production of a protein crucial for brain function. As a result, people living with Angelman syndrome experience severe developmental and intellectual disabilities.

For more than a decade, February 15 has been designated as International Angelman Syndrome Day, a significant date as February is Rare Disease Month, and the day symbolizes chromosome 15. Angelman syndrome affects approximately one in 15,000 individuals in the United States—or about 500,000 globally—and like most rare diseases, there is currently no cure. Among the 10,000 known rare diseases, there are fewer than 900 FDA-approved treatments.

But researchers are hopeful that cures for Angelman syndrome and other rare diseases, such as the neurodevelopmental disorder known as H1-4 syndrome, are within reach. Yong-Hui Jiang, MD, PhD, professor and chief of medical genetics, and Jiangbing Zhou, PhD, Nixdorff-German Professor of Neurosurgery, are among researchers at Yale School of Medicine dedicated to the development of new gene-editing treatments that aim to correct genetic alterations underlying rare neurogenetic disorders. Jiang is also the director of the Yale National Organization for Rare Disorders (NORD) Center of Excellence.

We spoke to Jiang and Zhou about exciting new rare disease research and therapies on the horizon.

Jiang: As a clinical geneticist, working with rare diseases is part of my job. As a researcher, it was my choice to focus on rare diseases. The patients I see while working in the clinic motivate me to understand their conditions from the scientific perspective and figure out how to help them.

For most genetic diseases, there are almost no treatments that specifically target the genetic defects. With the application of new genome technology in clinics, we are successfully identifying the genetic cause of these diseases and diagnosing them, but we are often not able to actually offer the next step of treatment or intervention. A better understanding of how to develop treatments that target the genetic defect is our ultimate goal.

Zhou: I’m a biomedical engineer who mainly works on developing non-viral, gene-based therapies. I’ve been working in this area for over 16 years. I think gene therapy could be widely used for a lot of major diseases in the future. But at this stage, I feel that gene therapy is particularly suitable for rare diseases such as Angelman syndrome, because they often have a very defined genetic cause.

This is one of the reasons I have focused on rare diseases over the past few years. I’ve been collaborating with Dr. Jiang, who sees patients with genetic disorders every day. It’s a benefit for scientists like me to work with physicians or physician-scientists such as Dr. Jiang because they see the great clinical need for new treatments.

Jiang: There are a few aspects. One is that we want people to know that although rare diseases are rare individually, we estimate that there are about 10,000 rare diseases in total. So altogether, they actually are not rare. Almost one in 10 Americans is affected by a rare disease.

Second, although we know of 10,000 rare diseases, we only understand the cause of about half of them. For the other 5,000, we don’t even have names. As geneticists, we do a lot of rare disease research because almost 80% of rare diseases are genetic. But not every rare disease is genetic—that is also a common misperception.

The third is that there is a great unmet clinical need for families contending with a rare disease. But rare disease researchers have very limited resources. Almost 10,000 diseases are in need of research to better understand how to treat them, but not every disease gets resources from the government or any other sort of funding source. This can be very frustrating for a lot of families who have spent years trying to find a diagnosis, but in the end find very little information or help because there is so little knowledge.

Jiang: Yale has been one of the leading institutions for rare disease research for almost half a century. Our history started with Leon Rosenberg, MD, who was the founding chair of the department of human genetics back in 1972, and he led the first clinical genetics division at Yale New Haven Hospital. During his tenure at Yale, he was a pioneer in the rare disease field, particularly for what we call metabolic diseases, such as methylmalonic acidemia and homocystinuria.

Following Leon Rosenberg, Richard Lifton, MD, PhD, another former chair of the department of genetics, and many other faculty and clinicians at Yale also dedicated their research to rare diseases. Yale investigators have discovered genetic bases for several hundred rare genetic diseases. Those efforts helped lead to the creation of the Centers for Mendelian Genomics, supported by the National Institutes of Health (NIH), as well as the creation of the Yale Center for Genome Analysis.

Jiang: We’ve accomplished quite a bit, mostly in patient care. For example, we organize a rare disease event every year to promote public awareness of these diseases—especially rare genetic diseases—and educate attendees on how to recognize them. The event brings together leading experts and patient advocates who lead lectures and roundtables on new insights and ways to support the rare disease community. We were also awarded NIH Undiagnosed Diseases Network (UDN) Phase III funding to join UDN as a new Diagnostic Center of Excellence.

Jiang: The majority of rare diseases are genetic. Over the last 20 years—due to a new generation of genome technology in clinics, such as an exome sequencing method that was pioneered at Yale—we have diagnosed genetic rare diseases much more rapidly. However, the challenge is the treatment or intervention; almost 95% of rare genetic diseases have no available treatment options.

For all genetic diseases, the best treatment would be to correct the genetic mistake, which could potentially slow down or stop the disease progression and offer a cure. CRISPR-mediated genome editing technology [which is designed to modify an individual’s DNA] offers promise and hope. Two-thirds of all rare genetic diseases affect the brain, which is the most challenging organ for gene therapy.

That’s where we step in. We hope that the STEP platform can eventually apply to rare genetic diseases that affect the brain. We’re currently focusing on neurodevelopmental disorders like Angelman and H1-4 syndrome because of our expertise. But this technology could also eventually be helpful for many brain disorders, including neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease. It will have very broad applications.

Zhou: STEP technology is a non-viral, chemical-based delivery system developed here at Yale. I have not seen anyone else working on this type of delivery system. It’s unique in that it uses chemicals instead of other vectors such as viral vectors or nanoparticles—the two most commonly used vectors in the field—to deliver genome editors to the brain.

It seems that the STEP technology works well for many neurogenetic diseases. We have applied the delivery system to a few diseases, including Angelman syndrome and H1-4 syndrome, and our findings have been very exciting. We have been working together with the NIH to translate this technology to clinical use. Hopefully, we can achieve that in the next few years.

Zhou: We have an array of new technologies under development or under evaluation for correcting genes through either gene correction or epigenetic regulation. This will allow us to potentially treat many rare genetic diseases. Dr. Jiang and I are working on ways to treat Rett syndrome, ALS, and Alzheimer’s disease, among others. The advances in our technologies open the door to study many genetic, neurodevelopmental, and neurodegenerative diseases.

Jiang: Our goal is to be able to treat or cure every rare genetic disease. The FDA approved CRISPR genome editing treatment for sickle cell therapy in 2023—which is quite impressive since CRISPR technology is relatively new. So I have a lot of hope that our work will move fast over the next decade because of the success of the sickle cell program. But we do expect challenges. For instance, many of the critical steps required to navigate CRISPR technology from the bench to the clinic are new to the FDA, the NIH, the research community, and pharmaceutical companies.

However, we remain optimistic that society will address these issues accordingly. We hope that we will be able to deliver therapy for a few dozen of these diseases over the next five years in the clinic.

Zhou: I think that with advances in gene-editing technology, it will now be possible to treat many rare diseases, even through a one-time administration. Along with FDA regulation, there will be challenges in how to engineer our system for efficiency, specificity, and delivery. But we have seen a lot of progress in the field, and we are definitely optimistic about the treatment options that will be available in the next decade.

Jiang: CRISPR editing aims to correct the genetic mistake—often there is only one mistake in the entire genome. But the technology itself may cause what we call off-target events [in which the technology edits DNA at sites other than the intended target] that might cause harm in an individual’s genome. The question is first, how can we maximize the safety of our technology from the design perspective? And second, how do we assess off-target events in the clinical sense?

Another major gap is in resources. From beginning to end, the development of each biological drug requires tens of millions of dollars. And then, we have 5,000 rare genetic diseases now that are eligible for CRISPR gene-editing technology. But because the individual diseases are rare overall, pharmaceutical companies may not be interested in investing due to financial reasons.

Jiang: We have our Rare Disease Day celebration scheduled for February 21 on Yale School of Medicine’s campus. It will include families dealing with rare diseases, physicians from Yale School of Medicine and Yale New Haven Hospital who treat patients, and rare disease researchers from across campus. Rare diseases can affect any organ system. We want to raise awareness across the academic hospital community because we hope that other specialties will take interest in investing more in rare diseases in terms of clinical care and research.

Zhou: We’re lucky to have support from the NIH for our work on Angelman syndrome. It’s an exciting time, but hopefully there will be support and investments from other sources so that we can continue these programs and help families. Over the last couple of years, we have been supported by multiple philanthropy efforts that have helped offset some of these limitations.