The Three Frontrunners in the CRISPR Therapy Race

is the ultimate child star in the biomedical

Just six years old, the gene editing prodigy is now the subject
of multiple clinical trials that aim to push the lab tech into the
real world.

I can’t stress how abnormal this is: CRISPR’s
awkwardly-named predecessors—zinc-finger nucleases and
TALENS—suffered through “bench-to-bedside” hell as it took
more than a decade before they even got the FDA go-ahead for
clinical trials. In 2017, a 44-year-old man
received the first-ever dose of gene therapy
—in the form of
zinc-finger nucleases—that targeted a deficient gene in his

This type of gene therapy, called “in vivo” in
scientist-speak, is markedly different than the most common type
these days. So far, the only gene therapies on the market are

: a procedure targeting blood cancer that extracts a
person’s immune cells, genetically edits them within the lab to
boost their cancer-killing power, and then infuses them back into
the body.

In vivo gene therapy
is far more intimate: rather than
extracting a person’s cells, a gene editing mix is directly
injected into a person, with the hope of performing molecular
surgery with a single shot.

CRISPR is now making that possibility very real. With dozens of
efforts in the making
, from premature aging to obesity and
developmental brain disorders, here are the frontrunners beyond
CRISPR-based cancer therapy to watch out for.

Duchene Muscular Dystrophy (DMD)

This genetic disease strikes mostly boys as young as three years
old, and patients (1 in 3,500 males or 300,000 patients worldwide)
rarely live past 30, often dying of heart failure.

DMD patients lack a single gene that encodes dystrophin, a
shock-absorbing protein that is absolutely critical for muscle
structure and function. The disease is caused by an array of
mutations that generally cluster on a specific part of the

DMD is actually a counter-intuitive target for CRISPR: it’s
one of the largest genes in the body and the number of mutations
are vast. Given the amount of muscle we have, it’s also not clear
how the gene therapy can easily reach the entire body with a single

Yet so far, the preclinical trials have been incredibly

By 2013, multiple labs had
successfully fixed the gene
in test tubes using cells from
patients with the disorder. In mice, a team injected the CRISPR
system into a fertilized cell carrying the mutation and
transplanted the edited cell into surrogate mothers. The babies, at
a month old, had markedly better muscle function than non-treated
peers. Similar treatments after birth in mice also helped.

Then in 2018, a
packaged the CRISPR machinery into viruses
and injected
millions of copies into one-month-old dogs engineered to have a
dystrophin deficiency. Two received a jab in their legs, the other
two got a bloodstream infusion. The result? Eight weeks later,
CRISPR had upped dystrophin levels by over 50 percent in their legs
and more than 90 percent in their hearts.

For reference, scientists think a 15 percent boost in dystrophin
is enough to see significant benefits, or can even be considered a
cure. This first large-animal, in-body trial shockingly found no
apparent side effects. A group of happy, jumping, gene-edited
puppies pushed scientists into further exploring the treatment.

February 2019
, a team found that a single injection of the
CRISPR machinery in mice with DMD boosted their muscle function for
well over a year. Even more promising, although the team saw some
pre-existing immunity towards CRISPR, the same kind
potentially present in humans
, the immune response didn’t
trip up the editing efficacy or trigger dangerous immune reactions.
Last week,
a study
found that tweaking the ratio of the two CRISPR
components can further up the efficacy.

Compared to a popular
previous experimental approach
that requires ongoing infusions,
CRISPR could be a one-time solution.

For pre-clinical data, these are remarkably strong. Exonics Therapeutics, a startup based
in Massachusetts, is looking to rapidly churn these results into
clinical trials. It’s perhaps one of the fastest-moving CRISPR
clinical applications.

Inherited Childhood Blindness

Hot on DMD’s heels is a CRISPR-based therapy that hopes to
eliminate—deep breath—Leber’s congenital amaurosis type 10.
Known as LCA10, it’s the most common form of inherited blindness
in children.

, Editas Medicine, along with its partner Allergan,
received the FDA green light to start pushing for a phase 1/2 trial
with a gene therapy dubbed EDIT-101.

Arguably, the eyes are an easier target than muscle. EDIT-101 is
designed to correct a single letter mutation in the CEP290 gene,
which screws up the structure of a certain protein in the
light-sensing cells in the retina. Remarkably, its function isn’t
precisely understood—scientists just know that correcting the
faulty gene restores vision.

In a
published in January 2019, the Editas team published
preliminary results in Nature Medicine, a rather surprising move
for a biotech company. Test tube experiments in human cells and
retinal tissue solidified that the CRISPR tool, EDIT-101, worked
without a hitch. In engineered mice harboring the mutation,
EDIT-101, following a jab into the eye behind the retina, rapidly
edited the mutated gene.

Even better news: a virus carrying the tool specifically
developed for primates edited the mutated gene in their cells at a
level that “met the therapeutic threshold,” the team said.

The results are encouraging Editas to move ahead full-steam,
gunning to release the first in vivo CRISPR cure. In the second
half of 2019 they are expecting to enroll between 10 to 20 patients
with LCA10 for a phase 1/2 open-label study. That is, the team will
gauge both safety of the treatment—retinal
are a potential side effect—and begin to assess its

Honorable Mention: Sickle-Cell Disease

Similar to the above two disorders, sickle-cell disease is
caused by a mutation of a single DNA letter. The results are
devastating; red blood cells become deformed “sickle” shapes,
which clog up blood vessels and cause life-long, sometimes
excruciating pain that’s often debilitating.  Roughly 250,000
kids around the world live with the disease.

Scientists have understood the cause of the disorder for over 60
years, but CRISPR means they can now do something about it.

A study
in 2016 in mice found that after CRISPR cuts the
genome, a small DNA sequence carrying the correct gene sequence can
repair the defective gene by roughly 25 percent—a relatively
small increase, but perhaps enough to alleviate symptoms.

The therapy here isn’t in vivo; rather, it’s similar to
CAR-T in that cells are edited outside the body. In this case, the
cells are stem cells nestled inside bone marrow—precursors that
eventually turn into blood cells.

Another approach
that recently received the go-ahead from the
FDA doesn’t directly try to change blood cells, either. Pioneered
by Vertex Pharmaceuticals and CRISPR Therapeutics, the study is
recruiting about 12 people with severe sickle-cell disease.
Scientists are using CRISPR to give the patients’ blood stem
cells a protein called HbF, which is a natural protein present at
birth that is especially potent at carrying oxygen, which
“sickled” red blood cells struggle with.

Rather than replacing the defective gene, the trial hopes to
alleviate symptoms by giving the body another oxygen-carrier.

The drug,
in the FDA’s fast-track development program
that supports
serious untreatable diseases, will be given just once to patients
to gauge its safety and preliminary effectiveness.

Of these three non-cancer CRISPR therapies, the first to hit the
market will mark a historical turning point for gene therapy and
for medicine as a whole: to efficiently edit the very base code
that makes us who we are. And it will save millions—while making
millions—in the process.

Image Credit:
Alpha Tauri 3D Graphics

Source: *FS – All – Science News 2 Net
The Three Frontrunners in the CRISPR Therapy Race