In late January, the FDA approved a clinical trial that could change the fate of humankind, beginning right at the cellular level. Scientists hope that the promising gene-therapy trial will reverse aging by restoring cells to behave like their younger selves. Now, the first person has received therapy for glaucoma in the trial, as announced by the company sponsoring it, Life Biosciences in Boston, Massachusetts.
The clinical trial is testing a technique that took the stage exactly two decades ago— cellular reprogramming. The idea is to restore a specialized adult cell to its embryonic state, such as a stem cell, or to directly convert it into another cell type, like a neuron. Shinya Yamanaka pioneered the technique in 2006, and in 2012 he received the Nobel Prize in Physiology for his groundbreaking work.
Pieces of Cellular Reprogramming
Every cell locks into a specific, adult type through on/off switches that determine which proteins are made inside a cell and how it behaves. These genetic switches are called transcription factors. However, Yamanaka factors are four special transcription factors that, when introduced into an adult cell, can revert it to a stem cell that can then differentiate into any other cell type.
- Oct4 and Sox2 are the core pair that maintain pluripotency (the ability to differentiate into any cell type) and prevent the cell from differentiating into a specific cell type.
- Klf4 prevents apoptosis or cellular suicide pathways.
- The final piece is c-Myc, which helps cells to multiply rapidly and bypass normal growth checkpoints.
Out of these four factors, only three have been implemented in the treatment. Currently, the scientists hope that proteins encoded by the genes will help regenerate the neurons in the optic nerve and repair damaged retinal cells. These neurons are normally unable to regenerate. Since the stakes are high, the clinical trial can be pivotal in ushering in a new area of medicine that scientists argue could be further refined to rejuvenate organs.
Designing the Clinical Trial
Pre-clinical studies in non-human primates demonstrated that ER-100 is well tolerated and safe, making it suitable for human trials. Life Biosciences will conduct the first-in-human trial to test the ER-100 gene therapy to rejuvenate damaged retinal cells in people with serious, age-related eye diseases. In the first phase of the trial, the therapy will be administered in people with glaucoma. The trial’s primary focus is on the safety and tolerability of the drug. In the clinical trial, Life Biosciences intends to treat as many as 12 people with glaucoma.
ER-100 uses Oct4, Sox2, and Klf4 to rejuvenate damaged cells while maintaining their commitment to their original function. The last factor, c-Myc, which is associated with uncontrolled growth, has been excluded from the therapy to lower the risk of tumors, which has historically concerned researchers and clinicians. Testing the therapy for an eye condition is safe because the eye is relatively isolated from the rest of the body, reducing the risk of life-threatening side effects.
To deliver the genes into the retinal ganglion cells, the researchers have chosen a virus commonly used as a shuttle or vector, whose arm-like axons make up the optic nerve. As an added safety measure, the system is designed to allow the genes to be switched on or off. When a participant takes the antibiotic doxycycline, the genes are switched on; when they stop taking it, the genes switch off. Scientists use this strategy to gain more control over how long they want the genes to be expressed. Leaving the gene active longer than necessary for rejuvenation can lead to other complications.
“Reprogramming has a big upside if it can be used safely in people,” says Matt Kaeberlein, co-founder of Optispan, a longevity-focused preventive medicine company in Seattle, Washington. “The technology is still really early, and the potential for catastrophic side effects is high.”
Is this a Therapy for a Longer Life?
Success in the trial can be life-changing for people with glaucoma. Almost 1–2 patients out of every 10 diabetics get glaucoma, while adults with diabetes are twice as likely to develop open-angle glaucoma. However, whether the modified ‘younger’ cells will enhance longevity is a big “what if?”. Right now, the company wants to address one age-related disease at a time rather than perform a full-body rejuvenation. Right now, Life Biosciences is testing cell reprogramming in animal models of liver disease.
Researchers at the University of Barcelona also applied cellular reprogramming to rejuvenate brain neurons in mice, which so far looks promising for treating Alzheimer’s, Parkinson’s disease, and other neurodegenerative conditions, provided it proves safe for therapeutic use.
The idea of beating biological constraints to achieve an enhanced body free from catastrophic diseases through technological advancements might have seemed fiction half a century ago. However, with key innovations in medicine, we are inching closer to a body that stays in peak condition even as we age. Transhumanism is an ambitious school of thought that seeks to enhance humans to the point that they evolve into a better version of themselves—a posthuman. While evolution in previous days was random, modern biology can give us a chance to be exempt from the genetic lottery.
Cellular reprogramming and de-aging cells are just one of the many pieces that can tilt the odds in our favor.
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