In many ways, 2023 could be described as a watershed year for gene and cell therapies worldwide. The outlook for patients with rare diseases is brighter than ever. By the end of the year, as many as 13 new cell or gene therapies could gain approval in the US and Europe, marking an unparalleled leap in advancements for the sector. Patients, who once faced death, disability, or reduced quality of life due to serious illnesses, now find hope in transformative therapies like CAR-T, which cured Emily Whitehead of her leukemia. The rapid acceleration in the pipeline of transformative therapies is evident with over 2,000 ongoing clinical trials, 200 of which are in Phase III, potentially heralding a future where many more patients will benefit from durable and possibly curative treatments. This article explores these innovative approaches to intractable illness and disease.

The FDA approved the first gene therapies in the United States in 2017 –Chymera and Yescarta–both chimeric antigen receptor T-cell (CAR-T) therapies. They deliver a gene to cancer patients’ white blood cells in order to program them to attack specific cancer cells. CAR-T treatments involve removing a patient’s white blood cells, programming them to contain a cancer-destroying gene, and then re-administering them to the patient.

Just before the end of 2017, the FDA approved therapy for a rare form of inherited blindness. Developed by Spark Therapeutics (Philadelphia, PA), Luxturna is the first gene therapy to target a genetic disorder. It’s also first in another significant way. Unlike the new cancer treatments, patients receive Luxturna directly via subretinal injection.

The blindness treated by Luxturna is known as “biallelic RPE65 mutation-associated retinal dystrophy.”

• Biallelic: Pertaining to both copies of a particular gene (allele)
• RPE65: A protein in the retina that helps convert light into the electric signals the brain interprets as sight
• Retina: Light-sensitive tissue in the eye
• Dystrophy: Wasting of tissue

The corrected version of the RPE65 gene helps repair patients’ retinal health and vision.

Clinical trial participants’ vision loss ranged from mild to severe. The trials included patients from ages four to forty-four. For 93% of them (27 out of 29), Luxturna treatment improved patients’ visual function, as shown by a “multi-luminance mobility testing (MLMT) score.” The MLMT measures the ability to navigate an obstacle course in low light.

Luxturna is priced at $425,000 per eye. Most patients need treatment in both eyes. Its expense partly comes from the nature of the treatment as a one-time cure. Spark Therapeutics is discussing payment options with insurers to help allay the sticker shock. One plan in the works with Pilgrim Health, a large non-profit New England-based insurer, hinges on outcomes. If the treatment fails to meet the intended outcome at certain post-treatment intervals, Luxturna will refund the treatment’s cost. Another proposal in the works would allow insurers to spread payments out over multiple years.

Scientists have adapted some viruses to transport therapies by tweaking them to target disease instead of causing illness. These souped-up microbes are known as viral vectors. They are the vehicles that make genetic therapy like Luxturna possible. The virus itself is simply a segment of genetic material— RNA or DNA—surrounded by a protein coat. Proteins on the surface of the vector (the modified virus) target proteins on a patient’s specific diseased or malfunctioning cell surface. These viral vectors then incorporate DNA into the patient’s genome by “tricking” the patient’s cells into producing the DNA it delivered. Ultimately, this enables a patient to make the functional protein that he or she lacks.

Over a decade ago, gene therapy stalled because of safety concerns. Researchers could not initially control the insertion point of modified genes. In some cases, the introduced genes disrupt patients’ other genes, causing serious illness. Researchers have now developed vectors that allow them to more precisely target where a therapeutic gene goes into a person’s genome, making the treatment much safer because it doesn’t interfere with the function of critical genes.

The most commonly used type of viral vector for gene therapy applications are adeno-associated viruses (AAV). However, AAVs aren’t the only vector in town. Lentiviral vectors are also being tested in gene therapy clinical trials. The choice of vector depends in part on the target tissue and the size of the genetic payload. AAV vectors so far seem to be best at targeting eye and muscle tissues. At the same time, there is some evidence that lentiviral vectors are better at targeting blood and central nervous system tissues. Lentiviral vectors also have a higher carrying capacity, so they may be preferred for very large genes or in cases where the goal is to deliver more than one gene.