Imagine only being able to perceive the world around you in shades of light and dark.
This is what Mike experiences on a daily basis, having been diagnosed with retinitis pigmentosa
since he was 18 years old.
Mike inherited the disease-causing mutation in a gene from his parents, with this mutation
causing the light sensitive portion of his eye known as the retina to degenerate, leading
to problems with his vision.
Unfortunately for Mike and the over 2 million people affected by retinitis pigmentosa, no
approved cure exists, but with optogenetics, that may become a reality.
But before we discuss this technique of gene therapy, let’s understand how the eye normally
works.
When light enters your eye, it passes through the cornea, pupil, then the lens, with the
cornea and lens working together to focus the light onto the retina, a layer of thin
tissue that covers the back of the eyeball and converts light into electrical signals
that are sent to the brain via the optic nerve.
The retina is the part of the eye affected by retinitis pigmentosa, so let’s have a
deeper look.
What we see are several different cells that act as a pathway for which light is converted
into electrical signals.
The first cells in this pathway are the photoreceptor cells at the back of the retina.
They are covered in light-gated ion channels known as rhodopsins.
When light hits the rhodopsins they open, allowing sodium ions, which are positively
charged, to enter the cell.
The charge within the cell increases until an electrical signal, or action potential,
is released and carried by the bipolar cells to the retinal ganglion cells, where the electrical
signal continues to the brain via the optic nerve.
The experimental treatment Mike underwent is known as optogenetic therapy, a technique
consisting of two steps: firstly, the introduction of genes, then the controlling of the gene
product through light signals.
The first step uses an adeno-associated viral vector, a genetically engineered virus, to
deliver genes that encode for a rhodopsin known as ChrimsonR to the retinal ganglion
cells.
The purpose of this is to integrate the function of the photoreceptors into the retinal ganglion
cells.
This bypasses any damage that has occurred before it in the signal pathway due to retinitis
pigmentosa.
The viral vector contains a single-stranded DNA genome that contains four main parts.
Firstly, the transgene, the gene that will be expressed, in this case, producing ChrimsonR.
Downstream from it is the promoter, which increases the expression of the transgene.
At the end, there is the terminal region which also assists in promoting the transgene.
These three sequences are flanked by two inverted terminal repeats that are essential for integration
into the host cell genome.
The viral vectors were delivered into the eye with an injection containing a dosage
of 50 billion viral vectors.
After the viral vectors infected the retinal ganglion cells, the DNA genome continued to
the cell nucleus and integrated itself into the host cell genome.
Now, the retinal ganglion cells can produce ChrimsonR on the cell membrane and respond
to amber light.
The second step is controlling the activity of ChrimsonR, the gene product, with light
signals.
Now that Mike’s retina can respond to amber light, a special type of goggles was worn
that uses a camera to convert his surroundings into flashes of amber light which were then
projected onto his eye.
Then, the retina works the same as what we saw before, converting light into electrical
signals.
What the researchers found was a truly amazing partial restoration of vision in Mike.
Before putting on the goggles, Mike could not identify where a notebook was on a table
in front of him.
But when he put the goggles on, Mike could perceive, locate and touch the notebook almost
every single time.
There were also meaningful improvements to his daily life such as being able to find
furniture in a room or a door in a corridor, but they were only seen when he was wearing
the goggles.
As you can imagine, injecting something artificially produced and foreign to the human body can
cause an unwanted immune response.
To ensure the treatment was as safe as possible, a proof of concept was done on a different
primate, the crab-eating macaque.
In that investigation, the team concluded that a dosage of 50 billion viral vectors
did not cause a significant immune response in the macaque.
As such, Mike received the same dosage, also with no significant immune response or side
effects.
Additionally, the same study on macaques influenced the design of the viral vector, with the team
finding that the expression of ChrimsonR increased when the transgene also encoded for tdTomato,
another protein.
This resulted in a more effective viral vector.
This study on Mike was the world’s first peer-reviewed documentation of partial visual
recovery in a patient with a late-stage inherited retinal disease.
It is the culmination of years of studies in animals such as the macaque and whilst
those successes should be celebrated, a successful clinical trial in a human is a massive improvement
over the past.
This study gives us tangible evidence that optogenetic therapy is successful in humans
and hope that future studies can improve the lives of people such as Mike suffering from
inherited diseases.