Gene Therapy's Giant Leap: From Rare Conditions To Common Cures

Gene therapy is a medical field that aims to treat or prevent diseases by modifying the genes within a patient's cells. It often uses vectors, typically viruses, to deliver therapeutic genes into target cells. The concept of gene therapy is to fix a genetic problem at its source. This quickly developing medical segment brought so many exciting novelties in the past year (even in the past few days) that we wanted to provide an overview of the most important milestones from the recent period.

Let’s start with a short overview of what gene therapy is and what the basics are worth knowing about these cutting-edge treatments. 

Gene therapy has various forms, including 

• Gene replacement: for diseases caused by a single faulty gene, gene therapy can provide a working copy of that gene to restore normal function. An example of this is Luxturna, which treats Leber's congenital amaurosis, a form of inherited blindness, by providing a functional copy of the RPE65 gene.
• Gene augmentation: this broader category involves adding new genes to cells, either to replace faulty ones or to enhance cellular functions. An example is Zolgensma, which treats spinal muscular atrophy (SMA) by adding a functional copy of the SMN1 gene to replace the missing or nonfunctional one, thereby restoring muscle function.
• Gene silencing: for diseases caused by overactive genes, therapy can "silence" those genes to reduce their harmful effects. An example is Onpattro (Patisiran), which treats hereditary transthyretin-mediated amyloidosis by using RNA interference to silence the TTR gene, reducing the production of the harmful amyloid protein.
• Gene editing: technologies like CRISPR allow scientists to edit the genetic code to correct mutations. Casgevy is the first approved CRISPR-based therapy, receiving regulatory approval in 2023 for sickle cell disease.
• Prosthetic gene therapy aims to enable cells to take on new functions that they do not naturally perform. One example is vision restoration gene therapy, which aims to restore vision in patients with end-stage retinal diseases by delivering light-sensitive proteins into the remaining cells of the retina, rendering them light-sensitive and enabling them to signal visual information to the brain. No approved therapies exist yet, but promising research is underway.

The method of delivery can be categorised into two main approaches: 

• In in vivo gene therapy, a vector (typically, a virus) is introduced to the patient, which then achieves the desired biological effect by passing the genetic material (e.g. for a missing protein) into the patient's cells.  
• In ex vivo gene therapies, such as CAR-T therapeutics, the patient's own cells (autologous) or healthy donor cells (allogeneic) are modified outside the body (hence, ex vivo) using a vector to express a particular protein.

Gene therapy is classified into two types by the type of cell it affects: 

• Somatic cell therapy (SCGT) affects non-reproductive cells and is not inherited by offspring. 
• Germline gene therapy (GGT) affects reproductive cells and can be passed down. Countries like Australia, Canada, Germany, Israel, Switzerland, and the Netherlands prohibit GGT in humans due to ethical concerns.

The delivery of DNA into cells can be accomplished by multiple methods: 

• Viral vectors: recombinant viruses, often preferred for their efficiency and specificity
• Non-viral methods: naked DNA or DNA complexes, offering lower immunogenicity

It is impossible to paint a comprehensive picture of this complex field without writing a novel, so we decided to focus only on the latest developments, to show the most recent updates and peek into the near future, estimating the immediate progress.

The first regulatory approval in the world for a CRISPR-based therapy

Casgevy, from Vertex Pharmaceuticals and CRISPR Therapeutics was approved in November 2023 in the United Kingdom for treating the blood disorders sickle cell disease and beta thalassemia for patients 12 and older. This is a one-time treatment, and here is how it works: 

"Casgevy is made by collecting a patient’s stem cells from the bone marrow. In a lab, CRISPR is used to edit a gene in those cells to produce high levels of fetal hemoglobin. Before these modified stem cells are administered, a conditioning regimen is required to kill the remaining cells in a patient that are making faulty hemoglobin. Infused into the patient, the modified stem cells make their way to the bone marrow.

Patients may need to remain hospitalized for at least a month while those cells take up residence in the bone marrow and start producing red blood cells that incorporate fetal hemoglobin."

The FDA approval came about a month later, also clearing Lyfgenia, which uses a lentiviral vector for genetic modification and is approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events. 

The latest FDA-approved treatment is Tecelra, a gene therapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma. Tecelra is also the first FDA-approved T cell receptor (TCR) gene therapy, administered as a single intravenous dose.

A baby born deaf can hear after breakthrough gene therapy

Opal Sandy was born with a rare genetic condition, auditory neuropathy, and was completely deaf due to the disruption of nerve impulses traveling from the inner ear to the brain.

She was the first patient treated in a global gene therapy trial, and within four weeks of having the gene therapy infusion to her right ear, Opal responded to sound, even with the cochlear implant in her left ear switched off. The 24-week checkup confirmed close to normal hearing levels for soft sounds, such as whispering, in her treated ear.

According to the reports, at the age of 18 months, the baby girl was able to respond to her parents’ voices and started saying basic words, such as “Dada” and “bye-bye.”

Along very similar lines, a research team from China reported that six kids with a type of hereditary deafness received an experimental gene therapy injected into one of their ears. Five out of the six children experienced significant improvements in their hearing, with their auditory thresholds improving by 40-57 decibels. This enhancement in hearing ability also led to improved speech perception in these children.

Small-scale human trial shows promise in lowering cholesterol

Following the previous, existing use cases of gene therapies, it is worth discussing what potential we see in this area. The next examples are not patient-ready innovations yet, but show how versatile help we can expect from these technologies.

While the VERVE-101 trial only included 10 participants with heterozygous familial hypercholesterolemia (HeFH), which causes lifelong high levels of low-density lipoprotein (LDL) cholesterol, the interim results are promising. 

The trial used a treatment called VERVE-101, which involves a one-time injection that permanently deactivates the PCSK9 gene in the liver. This gene is known to regulate LDL levels, a significant contributor to heart disease. By turning off PCSK9, the treatment successfully reduced LDL cholesterol levels by up to 55% in participants.

This was a Phase-1 trial so there is still a long way to go, but imagine the possibilities of having a one-time injection that could get rid of high cholesterol for good! 

Gene therapy relieves back pain and repairs damaged discs in mice

Here is an interesting new area for gene therapies! If you suffer from back pain due to a damaged disc, this might be great news for you. It seems it works in animal studies:

"Scientists engineered nanocarriers using mouse connective-tissue cells called fibroblasts as a model of skin cells and loaded them with genetic material for a protein key to tissue development.

The team injected a solution containing the carriers into damaged discs in mice at the same time the back injury occurred."

It's one thing that gene therapies have been proven to be effective in certain genetic conditions (even though they are incredibly expensive), but how about relieving back pain? 

The costs will determine the success and accessibility

As the examples above show, we have seen incredible progress in gene therapies in the past decade, with many exciting results emerging just in the last year. From treating rare genetic disorders to targeting more common conditions, the potential of gene therapy has expanded remarkably. Looking ahead, the future of gene therapy is even more exciting, with applications extending into broader fields that impact millions or even hundreds of millions of people. 

However, these treatments are still incredibly, frighteningly expensive, so we cannot expect widespread use in the short term. 

The world’s most expensive drug is the FDA-approved gene therapy, Libmeldy, with a staggering $4.25 million for a one-time treatment. Hemgenix, with its $3.5 million price tag was the record holder before, but gene therapies like Skysona ($3 million)and Zynteglo ($2.8 million) are not cheap either. Zolgensma has a price of $2.1 million per one-time treatment. Compared to these Luxturna seems like a bargain at $425,000 per eye / $850,000 per patient. The price of the latest approved gene therapy, Tecelra, has a list price of $727,000 for the one-time treatment.

This is why research targeting more common conditions is particularly intriguing. By focusing on treatments for widespread health issues, we may eventually develop therapies that are accessible and affordable for everyone.