Historically, gene therapy has been used to treat single gene genetic disorders. But today, their application is much broader… …cancer treatment, congenital blindness, predisposition toward depression. Even night vision.
What is Gene Therapy?
Gene therapy is the practice of uses viruses or bacteria to treat an illness or disorder.
Unlike chemical or antibody medicines, which affect the entire body, these living medicines can be targeted to a specific location. This specificity is crucial when seeking to replace other treatments such as chemotherapy.
Chemotherapy is like carpet bombing an entire area of cells in an effort to kill the mutated ones. Living medicines are like a sniper, painting a target with a laser so a drone can conduct a precision strike.
Beyond the obvious benefits of advanced treatment options for cancer, blindness, and organ replacement, gene therapy has huge upside potential.
It could help us treat disorders like autism, autoimmune diseases like celiac, and even give us access to new longevity benefits.
So How Does it Work?
Flash back to your honors biology class with me for a moment.
DNA
Is a double helix polymer that stores the info needed to create healthy cells.
Each strand of DNA is made up of these four bases:
cytosine
guanine
adenine
thymine
and are held together by hydrogen bonds. The different combinations of these bases are what codes people for certain dominant or recessive traits.
RNA
RNA is similar to DNA, but is not used for long-term storage. RNA is synthesized from DNA by an enzyme and acts as an intermediary, carrying the important DNA information from the nucleus of your cells to your ribosomes.
Your ribosomes create polypeptides (amino acid protein chains), which help create healthy cells. And healthy cells lead to a healthy human body.
If you’re missing a gene, or have a mutation present in a gene, then your DNA will transcribe an incorrect sequence onto your RNA.
And the RNA will do its job and bring that incorrect sequence to your ribosomes. And your ribosomes will replicate defective polypeptides. And that’s how you end up with a disorder or unhealthy human body.
Muscular dystrophy, Huntington's disease, Sickle cell anemia, Cystic fibrosis, Hemophilia, Cancer, these are all disorders and diseases caused by mutations.
And we can solve these problems by restoring a functional copy of the gene in question to restore or correct the specific mutation.
Think of it like restoring your phone or computer to a previous state after it's been infected by a virus.
Your DNA is like the code of a computer that executes what it’s been programmed to do. Using gene therapy, we can rewrite or restore that code to its correct state.
Modern Medicine
The first era of modern medicine
Began with your parents or grandparents and was defined by chemical medicines.
People discovered that consuming a specific leaf could alleviate a stomachache or something like that. This led to the realization that the active chemical compound in such leaves could be isolated and produced in large quantities in labs.
Think of something like aspirin, which is a synthetic compound, created to mimic the active ingredient in willow bark (salicylic acid).
Nearly every drug you’ve ever taken in your life, especially those found in over-the-counter pharmacies, belong to this category.
These chemical medicines work by being ingested, dissolved in stomach acids, absorbed by the bloodstream through the GI tract, and then binding to and affecting various proteins throughout the body.
The Second Era Introduced Antibody Drugs like Humira
Which work by targeting specific proteins in the body to treat various inflammatory conditions known as autoimmune diseases.
Humira is an antibody drug that recognizes and binds to a specific protein called tumor necrosis factor (TNF-alpha), which is elevated in patients suffering autoimmune diseases like rheumatoid arthritis, psoriasis, and Crohn's disease.
Humira helps reduce inflammation and control the immune response of autoimmune disorders.
The Third Era of Modern Medicine
Where we are now, focuses on "living medicines." This includes the use of viruses, bacteria, and cells—elements that are "alive"—to induce changes in the body.
Real Life Use Cases Today
Congenital Blindness
One real-world application of these advancements can be seen in a clinical study for congenital blindness. This study focused on patients with a rare form of inherited genetic blindness called Leber's congenital amaurosis.
These patients are born essentially blind, and struggle with navigation and visual acuity, especially in low light conditions.
The patient in the above video took 214 seconds to navigate the maze pre-treatment, because they were born without a specific gene.
All they needed was a single “living medicine” viral treatment to receive the protein they were missing.
This same young patient has now gone on to get their driver's license. They are they are now, quite literally, walking among us, leading a completely normal life.
AAV Cancer Treatment and Sting Agonists
Cancer is just a mutation in one of our cells where instead of doing what’s its told, it starts to replicate out of control. When we’re younger, our immune system recognizes these abnormal cells and Natural Killer Lymphocytes eliminate them.
But as we age, the immune system's ability to recognize and eliminate cancerous cells declines. The current research speculates this is due to the accumulation of genetic mutations in cells over time, which can make cancer cells less visible to the immune system.
And if allowed to progress to a tumor, such a tumor can create an immunosuppressive environment, allowing cancer cells to evade immune detection and attack altogether.
Companies like the Japanese startup, TKG Therapeutics Inc, the British biotech company GlaxoSmithKline, and UC Berkeley spinout company Audro Biotech Inc, are all working to make a “living medicine” viable treatment option for the hundreds of thousands of people who suffer from cancer each year.
Specifically, STING (Stimulator of Interferon Genes) Agonists have shown promise in enhancing the antitumor response. Going back to our military example, we can paint the tumor as a target and stimulate the body’s natural immune response.
Siren Biotechnology is pioneering "Universal AAV Immuno-Gene Therapy" which combines the power of adeno-associated viruses (AAV) gene therapy and cytokine immunotherapy (via Sting Agonists) into a single transformative treatment option.
Siren's approach aims to overcome the delivery, efficacy, and toxicity challenges associated with traditional cytokine immunotherapies listed above by leveraging the unique properties of AAV gene therapy.
Click → here to learn more about Sting Agonists and → here to learn more about AAV gene therapy.
So by using gene therapy, we can paint a tumor as a target to be destroyed, and then step back and let the body’s natural immune system do its job.
Crispr-Cas9 and Xenotransplantation
On March 21, 2024, a pig kidney was genetically-edited using CRISPR-Cas9 technology by eGenesis of Cambridge, Massachusetts, to remove incompatible pig enzymes and add human proteins to improve its compatibility with the recipient.
Mass General announced it had successfully performed the first transplant of the genetically-edited pig kidney into a living patient. This marks the most recent in a string of wins for CRISPR-Cas9 gene editing.
As you might imagine, transplanting an organ from one species to another presents complications. From immune rejection, to cross-species virus transmission.
For example, in 2022, doctors at the University of Maryland performed the first successful xenotransplantation of a pig heart into a human patient. And in September 2023, the second transplant was performed. Both patients remained alive for roughly two months each, before passing away.
eGenesis, the company behind the most recent kidney transplant, is betting that it can overcome these challenges by better editing the genes in these organs to remove the incompatible pig genes to improve compatibility among humans.
This would be a huge win. There’s a dramatic shortage of human organs needed for transplant across the world. More than 100,000 people in the U.S. are waiting for an organ transplant and 17 people die every day waiting for an organ.
In China, hundreds of thousands of people suffer liver failure every year. And out of that number, only 6,000 received a liver transplant in 2022.
What’s Next?
Beyond the obvious benefits of advanced treatment options for cancer, blindness, and organ replacements, gene therapy has huge upside potential.
Autism
Autism spectrum disorders (ASDs) that are caused by mutations in single genes (monogenic ASDs), could be treated and cured using gene therapy techniques. Gene delivery using viral vectors to introduce a healthy copy of the affected gene has already been explored for conditions like Angelman syndrome and Rett syndrome.
Celiac
I bet you know someone who is gluten free, and not by choice. Celiac disease is considered a model autoimmune disease that could potentially benefit from gene therapy approaches in the future because it has a well-defined trigger (gluten) and a relatively well-understood pathogenic cascade.
Treatment Resistant Depression
Researchers have identified the LHPP gene as a potential target for gene therapy to help cure treatment-resistant depression. Modulating the expression of the LHPP gene, which is involved in regulating synaptic function, could help alleviate symptoms of depression.
Super Augmentations
Night Vision: By delivering a healthy copy of the GUCY2D gene, gene therapy was able to rapidly improve the patients' low-light sensitivity and rod-based night vision.
This suggests that gene therapy could be used in the future to enhance night vision capabilities in otherwise healthy people.
Reduce the Need for Sleep: There is a rare mutation that happens naturally in some patients. These are people already walking among us, who have a mutation in a gene called DEC2.
This mutation allows these patients to only need four hours of sleep a night to be completely rested the same way that we have the need for eight to nine hours of sleep.
By modulating this gene in otherwise healthy people, we could allow for these subjects to only need four hours of sleep as well. And we could do this with today’s level of technology.
Longevity: we could use gene therapy to regenerate the tissue in your joints, and get rid of things like cellulite and brain fog. We can’t do this today, but the timeline is five to ten years in the future, given our current rate of development.
The Big Picture
We should and have to be careful with gene therapy because humans are notoriously bad at being able to measure the second and third order consequences of our actions.
Simple examples include everything from DDT to Communism. When we try to plan ahead and control all the variables in a particular course of action, there are often negative latent functions that emerge.
In the DDT example, let’s use this case study: We wanted to kill mosquitos in Malaysia (formerly Borneo) to control a malaria outbreak.
While DDT effectively killed the mosquitoes and reduced malaria, it also had several unintended consequences:
It killed off a parasitic wasp that had been controlling a population of thatch-eating caterpillars.
Without the wasps, the caterpillar population exploded and began eating the thatched roofs of the Malaysian people's homes, causing them to collapse.
The DDT also accumulated in the bodies of insects, which were then eaten by geckos. The geckos, in turn, were eaten by the local cats.
The high levels of DDT in the geckos ended up killing the cats.
With the cats gone, the rat population in Malaysia surged, as the cats were no longer there to keep them in check.
The proliferation of rats led to outbreaks of plague and typhus, posing a serious threat to the Malaysia people.
To address the rat infestation, the World Health Organization initiated "Operation Cat Drop," where they parachuted live cats into Malaysia using the Royal Air Force.
The introduction of these cats helped restore the ecological balance and control the rat population, resolving the crisis caused by the unintended consequences of the initial DDT spraying.
While this is both a hilarious and tragic example, its easy to see how a top down decision with a specific objective led to a whole host of negative latent functions. We have to be careful about making genetic decisions that could have unintended consequences.
Conclusion:
Artificial Intelligence may help us think through the second and third order consequences of gene therapy. It could allow us to think through all of the variables in a way we never could do before and provide a road map of the possible benefits and pitfalls of conducting a specific course of action.
All that being said, gene therapy remains one of the most exciting areas of active research. And the good thing is, pharma is a heavily regulated industry, so this is unlikely to runaway and create adverse results.
Gene therapy is coming in your lifetime. The future is already here, it’s just not evenly distributed.
This is really interesting and gene therapy is really promising. But what do you think about the nth order effects of potentially altering a single gene? The body is an incredibly interconnected system. I can definitely see the potential in disease defined by single genetic defects... but might get trickier for multi-gene driven diseases