Dr. John Germiller at the Children’s Hospital of Philadelphia poses with his 11-year-old patient, … [+] who is now able to hear thanks to gene therapy.
Children’s Hospital of Philadelphia
It is now 12 months since the Food and Drug Administration rolled out the historic approval of a CRISPR therapy designed for patients suffering from sickle cell anemia and the blood disorder beta thalassemia.
From reprogrammed stem cells to next-generation gene editing, 2024 has seen some incredible developments with the potential to become new treatments for a range of chronic and inherited diseases.
Here are five new breakthroughs which I feel will hold the most promise in the years to come.
Groundbreaking Stem Cell Treatment Restores Vision
The fragile layers of cells that cover the cornea, the dome-shaped, outermost layer of the eye, can easily be damaged by burns, infections, inflammatory diseases of the eye and even side effects of certain drugs. This is a condition known as corneal epithelial stem cell deficiency, and it can lead to vision loss and, in particularly serious cases, blindness.
Previously most attempts to replace the cornea through donor transplantation have failed due to rejection by the immune system. However, last month, a paper in The Lancet described a world-first clinical trial conducted by a team from Osaka University, led by ophthalmology professor Kohji Nishida, which successfully treated four patients with severe corneal eye diseases using reprogrammed stem cells.
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Circular sheets of corneal cells, generated using induced pluripotent stem cells (iPS) derived from umbilical cord blood, were transplanted into four patients between the ages of 39 and 72 with corneal epithelial stem cell deficiency. The study showed that their vision has been restored, and the beneficial effects remain after four to five years of follow-up.
“We plan to initiate a larger clinical trial in the first half of next year,” says Nishida. “I believe that iPS cells can be used to treat other eye diseases, including corneal endothelial disease as well as retinal diseases such as retinitis pigmentosa.”
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Artificial Ovaries Are On the Horizon
According to the Centers for Disease Control and Prevention, 13.4% of women aged 15 to 49 have impaired fertility with causes ranging from conditions such as polycystic ovarian syndrome and endometriosis to the impact of certain medications.
For years, scientists have sought to tackle this through developing an artificial ovary, but this work has longer been hampered by a limited understanding of what it takes for an ovarian follicle to mature and produce an egg. Following puberty, women have approximately 300,000 ovarian follicles, with a small subset of them periodically activating and entering the growing pool, a process that repeats every month until menopause.
Earlier this year, scientists from the University of Michigan created the first “cellular atlas” of human egg formation by studying five donated ovaries using state-of-the-art cell and genetic mapping technologies. Through examining how the follicles move and change in structure as they progress through different maturation stages, the scientists identified key factors that enable a follicle to mature.
Ariella Shikanov, associate professor of biomedical engineering at the University of Michigan, who led the project, predicts that this understanding could lead to new treatments for polycystic ovarian syndrome and endometriosis and potentially even functional artificial ovaries.
“With this new knowledge of ovarian biology, we are better informed when we try to create artificial ovaries as a potential treatment of female infertility,” she says. “With the ability to guide follicle development and tune the ovarian environment, the engineered ovarian tissue could function for years and even delay menopause.”
CAR T-Cell Therapy Offers New Hope for Brain Cancer
With a median survival time of just 15 to 18 months, a diagnosis of glioblastoma, a rare and aggressive form of brain cancer, has often been regarded as akin to a death sentence.
This could change through CAR T-cell therapy, the groundbreaking method of reengineering a patient’s immune cells. It has already made a remarkable difference to the treatment of blood cancers over the past decade.
Earlier this year, researchers at Stanford demonstrated that infusions of CAR T cells into the brains of pediatric patients with brain cancer could offer new hope. At the same time, three other research groups have conducted studies that show benefits on imaging scans after infusing CAR T-cells into the brains of adult glioblastoma patients.
These results have already generated such optimism that Carl June, the renowned University of Pennsylvania immunology professor who helped pioneer the first CAR T-cell therapy for certain blood cancers, predicts that there will be FDA-approved CAR T-cell therapies for glioblastoma within five years. (I had the honor of speaking to June this year and wrote a separate column on his insights here.)
Bridge RNAs Represent the Next Generation of Gene Editing
While CRISPR promises to revolutionize the treatment of rare diseases caused by mutations in a single gene, experts are already pioneering gene editing’s next frontier.
Back in June, researchers at the Arc Institute, an independent nonprofit research organization that partners with UC Berkeley, Stanford, and UC San Francisco, published a paper in Natureunveiling the discovery of bridge RNAs as a way of regulating genetic transposition. This refers to the ability of DNA to jump from one place in an organism’s genome to another.
Patrick Hsu, co-founder of the Arc Institute, explained that this allows for a more complex kind of gene editing. Hsu says that while CRISPR can only make a “cut” in DNA, bridge RNAs make it possible to “cut and paste,” rearranging any two pieces of DNA to insert, flip or cut out a genetic sequence of interest in a single step.
This could have enormous implications for using gene editing to treat a much broader swath of diseases in the coming years. “Many diseases, chronic and acute, are driven not by a small number of nucleotides in one gene, but by larger-scale genetic variations such as missing, repeated or inverted genetic passages, often across a number of genes,” says Hsu. “Bridge RNA’s powerful and flexible editor may help us replace these disease-causing genetic sequences entirely.”
Gene Therapy Allows a Deaf Child to Hear For the First Time
Most of us have never heard of the otoferlin (OTOF) gene, but it plays an integral role in our ability to hear through the production of a protein which allows sounds to be communicated from the ear to the brain.
A small number of people around the world are born with an inherited mutation, which means that this gene is defective, leaving them so profoundly deaf that they have never heard a human voice.
Earlier this year, a team led by John Germiller, an attending surgeon at the Children’s Hospital of Philadelphia, unveiled results from a first-in-human gene therapy procedure that treated inherited hearing loss in an 11-year-old boy by placing a single, small dose of functioning OTOF genes in the cells of his inner ear.
OTOF is known as a particularly large gene, a characteristic that has previously been considered challenging for gene therapy, as such genes are too heavy to be carried by a single modified virus. However, Germiller and his colleagues split the gene into two separate parts, a “dual vector approach” that enabled it to be carried by the virus, and then reassembled within the patient’s cells.
The procedure worked with dramatic consequences. “Our first patient had never heard sounds in his lifetime,” says Germiller. “About two weeks after the experimental procedure, he began to notice sounds, which gradually grew in strength and clarity. Soon he could hear his father talking to him, and cars on the street in Philadelphia. It was very gratifying.”
According to Germiller, there has been considerable interest within the field in the success of the dual vector approach, creating the possibility of similar clinical trials for other genetic conditions such as retinal diseases where the genes involved have previously been thought to be prohibitively large.
I look forward to what will undoubtedly be more exciting medical advances in 2025!
Thank you to David Cox for additional research and reporting on this article.
Correction: An earlier version of this earlier incorrectly identified the Arc Institute as a part of the University of California, rather than an independent nonprofit research organization. The article has been updated.
