It’s Finally Time To Test Resetting The ‘Ageing Clock’ In Humans

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Partial reprogramming is a potentially revolutionary approach to treating age-related diseases and ageing in general. It works by erasing some epigenetic modifications – changes to the DNA molecule that alter how the DNA is read, without altering the genetic code itself. Partial reprogramming was first demonstrated over a decade ago, but scientists have been very cautions about human testing due to the risks involved. It now looks as though the first ever clinical trials of partial reprogramming are going to go ahead, as Life Biosciences recently announced that they had gained Investigational New Drug (IND) clearance from the US FDA for their experimental therapy, ER-100. The treatment will target optic neuropathies – diseases in which damage to the optic nerve leads to vision loss.

What Is Partial Reprogramming?

All non-reproductive cells within the body contain the same set of chromosomes, yet cells from different tissues function completely differently. This is thanks to epigenetic modifications that determine which parts of the genetic code are read and which parts are ignored. In 2006, researchers in Japan discovered a group of molecules that could erase those epigenetic modifications and thereby reset the ‘identity’ of a cell, turning it into a pluripotent stem cell. For this discovery, lead researcher Shinya Yamanaka won the Nobel prize for Physiology and Medicine, and the reprogramming factors he discovered were named ‘Yamanaka factors’.

Around the same time, scientists were becoming increasingly interested in the importance of epigenetic modifications in the ageing process. DNA acquires epigenetic modifications such as methylation (the addition of molecular ‘tags’ called methyl groups) semi-randomly over time, often as a result of the repair of damaged DNA. These modifications can cause genes to be overactive or underactive, or cause genes to be ‘switched on or off’ in a way that harms cellular function. Yet these age-related epigenetic modifications could now be reversed with Yamanaka factors, essentially resetting cells to a more ‘youthful’ state.

There was, however, a problem: Yamanaka factors also erased the epigenetic modifications that gave cells their ‘identity’ – the genetic settings that made a heart cell a heart cell and a brain cell a brain cell. Even if Yamanaka factors technically reversed epigenetic ageing, they could not be safely given to living organisms. However, scientists soon discovered something exciting: if Yamanaka factors were delivered to cells in limited doses, they could erase age related epigenetic modifications while leaving other modifications intact, preserving the identity of the cell. This was partial reprogramming.

A Decade of Progress

Partially reprogramming a cell in a lab is one thing, but achieving partial reprogramming in a living organism is a significantly greater challenge. It is much harder to control the level of exposure to Yamanaka factors inside the body, but it is possible with genetic modification. This is the approach researchers took in 2016, when they showed for the first time that mouse lifespan could be significantly extended by genetically engineering mice so that the genes that encode Yamanaka factors could be activated with drugs.

The type of genetic modification used in this study is not permitted in humans, so how could researchers translate these findings from animals to clinical trials? The answer was gene therapy.

The Therapy

The partial reprogramming method that will be tested in this clinical trial is based on previous animal research from David Sinclair’s lab. The team wanted to see if partial reprogramming could reverse vision loss in aged mice and mice with retinal nerve damage. Instead of altering the mouse genome, they used a viral vector to deliver new genes encoding Yamanaka factors into the target cells. These genes remained separate from the genome, and were packaged with a ‘genetic switch’ that meant that they would only activate when mice were given the antibiotic doxycycline in their drinking water. In this way, researchers could ensure that the cells that received the gene therapy only produced Yamanaka factors for just long enough to reset their age. In an effort to make the treatment safer, researchers also left out one of the Yamanaka factors called c-Myc. As well as c-Myc being able to cause cancer under certain circumstances, researchers had also found that removing this factor allowed them to keep the expression of Yamanaka factors active for much longer periods without fully reprogramming cells.

Remarkably, this approach appeared to work. The treatment improved the regenerative capacity of the damaged nerves within the eye and allowed them to repair themselves, resulting in improved vision.

The Trial

ER-100 will employ a similar approach – a gene therapy to deliver Yamanaka factor genes minus c-Myc, then eight weeks of treatment with doxycycline to keep those genes active. Enrolment is expected to begin by March, and the trial will enrol around one new patient each month so that any adverse effects can be closely monitored.

The green-lighting of this trial is a significant milestone for the field of partial reprogramming, as even if it is limited to a rather specific set of conditions, it shows that regulatory authorities are coming around to the idea of targeting fundamental epigenetic drivers of ageing in order to treat disease. It will give us an initial indication of the safety and potential problems with using partial reprogramming in humans, and could open the door to testing this therapy in many other diseases. Since partial reprogramming tackles what is believed to be a fundamental driver of ageing, the applications could be extremely wide-ranging.