Genes as Medicine | HHMI BioInteractive video

Molly had a vision impairment because when I was
breastfeeding Molly, she would look away from
me to see a light somewhere else in the room. MOLLY TROXEL: [BABBLING] Mm. JAMES BARRAT: When
their daughter was just a few months
old, Laura and Ryan Troxel got heartbreaking news. Molly had symptoms of
an inherited disease– a form of blindness. She would probably
lose what little sight she had by the time
she became an adult. RYAN TROXEL: Oh,
it was devastating. I remember crying. Still tear up now
thinking about it, just knowing that
your daughter’s not going to be able to see. JAMES BARRAT:
Molly’s blindness was due to a mutation in
the genetic instructions for a protein in her eyes. Ever since biologists first
cracked the genetic code, they imagined that someday
this knowledge would help cure diseases like Molly’s. SPEAKER 1: Bingo. JAMES BARRAT: That
time has finally come. JEAN BENNETT: When
I first realized that we could make
a blind dog see, it was the first hope
that we could actually do the same thing to children
and make blind children see. SPEAKER 2: And you did it! JAMES BARRAT: This is the story
of how gene therapy developed from a dream in the lab to
a revolution in medicine. [UPLIFTING MUSIC] JEAN BENNETT: Your
injections look fabulous. SPEAKER 3: Yeah. JEAN BENNETT: That
looks really exciting. SPEAKER 3: I have even more
encouraging stuff to show you, actually. JEAN BENNETT: I first began to
be interested in gene therapy when people began to clone genes
and transfer them to animals. This was in 1980. They were transferring
genes to mice and altering their
appearance and their growth. And I realized,
wow, this approach could be used to treat humans. Impressive. That’s great! And I realized this
is what I want to do. JAMES BARRAT: Most
genes are instructions for producing proteins that
perform important functions in different cells of the body. Inherited diseases come
from mutations in genes. Those mutations result in the
production of a faulty protein or sometimes no protein at all. The principle of gene
therapy is to provide cells with a corrected copy of
the mutated gene that will produce the functional protein. JEAN BENNETT: The big
idea of gene therapy is that you’re treating
a disease at its root. You are stopping the
disease in its track by altering the instructions
that the cell is given. The benefits are that
one can potentially correct the basic problem
that is causing the disease and allow the cells
to function normally and thus, allow the person
to function normally. I met my husband
in medical school, and he knew early on that he
wanted to study neuroscience, and his biggest interest
was in the retina. JAMES BARRAT: The retina
is a light-sensitive layer of neural tissue at
the back of the eye. It converts light
energy into signals that are carried to the
brain by the optic nerve. ALBERT MAGUIRE:
People don’t realize the retina is a very
integral part of the brain. And essentially, what
it is is the brain is squeezed out like toothpaste
into the eye sockets, and it forms a film, and
that’s the camera film– the retina that
you and I see with. JAMES BARRAT:
Maguire’s focus on eyes and Bennett’s
expertise in genetics naturally came together. SPEAKER 2: So just walk
right through there. JAMES BARRAT: In the 1980s,
while they were still students, McGuire wondered if blindness
might be treated with genes. JEAN BENNETT: Albert
asked me in medical school whether the eye would be a
good target for gene therapy, and I said, yeah, sure. What I didn’t tell him is, we
didn’t know any of the pieces that we needed to
be able to do this. There had been no genes
identified which, when mutated, caused that condition. We didn’t know how
to clone those genes. ALBERT MAGUIRE: If I had
known all the issues, I probably would
have walked away. JAMES BARRAT: It
would take decades to assemble the necessary
tools and know-how, but the eyes were a
good potential target for developing a gene therapy. Eyes are easy to access. And two eyes means
that in an experiment, one can be treated, while
the other acts as a control. For Bennett and Maguire,
the next question was, how can you get the
corrective genes into the cells you want to treat? JEAN BENNETT: It may seem
crazy, but viruses are now used because
viruses have evolved to do what they do really
well and that is to move DNA or RNA across cell membranes. JAMES BARRAT: Viruses contain
packets of genetic information. They can invade cells and
deliver their genes inside. Then they hijack
the cells machinery to make copies of themselves. Scientists strip away
the viruses harmful genes and those needed for the
viruses to replicate. Then they insert a copy
of a corrective gene. Attached to the gene
are regulatory sequences which directed to be
expressed in specific cells. Next, scientists
inject huge numbers of the modified viruses into the
tissue that needs the therapy. The viruses invade those cells
and deliver the corrective gene but without replicating. JEAN BENNETT: Our
first animal model for testing the
ability to use viruses to deliver DNA was the mouse. JAMES BARRAT: Through the 1990s,
Bennett and her collaborators tested different types
of viruses and methods for injecting them
into mouse eyes until they showed the
procedure could work. But mouse eyes are small
compared to human eyes. JEAN BENNETT: You can
imagine the surgery to deliver a gene to a mouse eye
is a lot different than if you were going to inject
the eye of a human which is 100 times bigger. JAMES BARRAT: To be sure that
a sufficient number of genes could be delivered and
expressed in human-sized eyes, the researchers needed
to develop procedures in a large animal model. JEAN BENNETT: Come
on, come on, come on. JAMES BARRAT: One
breed of dog turned out to be the perfect model. Briard shepherds have eyes
about the size of humans. And remarkably, some
Briard shepherds suffer from the same
form of blindness that’s the leading cause
of blindness in children. The couple adopted
this pair of dogs after they retired
from work in the lab. ALBERT MAGUIRE:
The Briard dog has the exact same genetic
condition as humans who have child-onset blindness
called Leber amaurosis. So they match up
almost perfectly with the human condition. JAMES BARRAT: In
both humans and dogs, Leber amaurosis can
be caused by mutations in a gene called RPE65. As a result of the mutation,
the light-detecting cells in the retina, called
photoreceptors, progressively malfunction and die. The symptoms typically
show up in infancy. Molly Troxel inherited the
disease-causing mutation from her parents. They each have one working
copy of the RPE65 gene, so their vision is fine. But in each parent,
the other copy contains a rare mutation that
leads to a nonfunctioning protein. Molly inherited two mutated
copies of the RPE65 gene– one from her mother and
one from her father– so her cells have no
functioning RPE65 protein. The odds of two people
with a rare mutation in the same gene having a child
together are remote, indeed. RYAN TROXEL: You know, her
and I, just somehow, our genes ended up creating Molly
which is a great thing. But with her having
the eye disease, it’s just a really
rare thing also. LAURA TROXEL: I think
Molly was around age six when they were able
to define that she had the RPE65 mutation. Gene therapy would be an
option for her someday, so that was a lot
of wonderful hope. JAMES BARRAT: The research that
could turn hope into reality came together with the
help of Briard shepherds. JEAN BENNETT: It wasn’t until
we had the Briard dog that we actually had all of
the pieces in place, the know-how of how
to deliver the genes, and the appropriate animal
model which is critical. JAMES BARRAT: But while
Bennett and Maguire assembled the components for treating
Leber amaurosis in dogs, researchers had already
begun testing gene therapies for other diseases on humans. In 1999, tragedy struck. Jesse Gelsinger entered
a gene therapy trial at the University
of Pennsylvania for the treatment of
a rare liver disease. Doctors injected Jesse
with a virus that carried copies of
a corrective gene, but his immune system
reacted to the viral invasion with overwhelming force,
damaging his organs. Four days after the procedure,
Jesse Gelsinger died. He was 18. JEAN BENNETT: This was a
tragic event for this young man and his family, but it was also
a tragic event for the field of gene therapy itself because
everything came to a screeching halt. People withdrew their
interest and their support for gene therapy. There was no more funding. JAMES BARRAT: With human
clinical trials shut down, Bennett and Maguire
pushed on with attempts to restore sight in
Briard shepherds. Dogs with mutations
in the RPE65 gene would grow up to be
blind, unable to navigate simple environments. JEAN BENNETT: So we took
advantage of all the things that we had learned over
the preceding decade or so and injected three puppies. JAMES BARRAT: Then they waited. Would the therapy restore
some sight to the dogs, or would failure
send the scientists back to the drawing board? JEAN BENNETT: At the two-week
time point after injection, I got a call from
the animal facility. The vet tech taking
care of them said, gee, they’re watching me as I
walk through the facility. I think they can see. And they could. And it was miraculous. It was absolutely just one
of the most exciting moments I’ve had in science. It was the first hope
that we could actually do the same thing to children
and make blind children see. JAMES BARRAT: Bennett and
Maguire and their collaborators successfully repeated the
experiments with more dogs. The next step would be
to try it in people. But in the wake of
the Gelsinger tragedy, moving forward with human
trials would be difficult. KATHERINE HIGH: There
had been a general sense that this was a therapy that
was not ready for prime time, that there were too many
things we didn’t understand, and that it was not
ready for development. All the companies that had
been involved in gene therapy were either turning away
from it or they were failing. And now they want
several examples of this. JAMES BARRAT: But as
companies left the field, gene therapy pioneers like
Katherine High persisted. In 2001, she was setting
up a gene therapy facility and looking for
candidate diseases when she came upon
Bennett’s work. KATHERINE HIGH: So
I was always looking for things where there
was good proof of concept in a large animal model,
and she clearly had it. SPEAKER 4: So I’m looking
at retinal ganglion cell. KATHERINE HIGH: When we
had our facility set up, I went over to talk to her. JEAN BENNETT: She walked into
my office, and I looked up, and she said,
Jean, how would you like to run a clinical trial? I was just– I was totally floored. I was not expecting that at all. And so that was the beginning
of a whole infusion of energy and enthusiasm and support
and led to incredible success. JAMES BARRAT: It took
Bennett and High years to adapt the virus
delivery system to be safe and effective in humans. In 2007, they recruited
the first patients for human trials. In 2013, the Troxels
threw a party for Molly. Now 11, she was about to be
enrolled in a later trial. MOLLY TROXEL: I was really
excited and a little scared because, you know, it’s
surgery on your eyes. But then I was thinking, you
know, it’s going to be OK. It’s going to work. LAURA TROXEL: Molly was gung-ho. She was going to do this. She wanted it. I was afraid. The hope was that she
would have more vision, but there’s a possibility that
it could make her vision worse. JAMES BARRAT: The surgeon first
injected one of Molly’s retinas with six drops of a
liquid containing billions of gene-carrying viruses. Later, if the
procedure worked, they would inject the other eye. Each virus contained a
copy of the RPE65 gene. The viruses invaded
the retina cells and delivered their
genetic payload. The cells machine
reproduced the RPE65 protein to restore function. When the patch came
off, Molly couldn’t tell if anything was different. But then– MOLLY TROXEL: I saw the moon. RYAN TROXEL: Well, wow,
Molly, you can see that? For her to see the
moon and stars, things you would take for
granted, was just huge for us. Now, there’s just
no stopping her. I think my biggest surprise for
me is just her independence. She could ride her
bike up in the circle without us being
right there and, you know, on pins and
needles that she’s going to hit a mailbox or something. LAURA TROXEL: She’s
hit a lot of mailboxes. Even though, to an outsider, she
still looks visually impaired, I’m so thankful that she can
see better, and if nothing else, that it stopped the
progression of this disease. RYAN TROXEL: Nice job. MOLLY TROXEL: I was
hoping for perfection, but that’s hard to do. But what I have now is perfect. JEAN BENNETT: I
feel extraordinarily lucky to actually see our
research move from the bench all the way to treating humans
and then see these humans benefit. SPEAKER 5: Good job, Molly. JEAN BENNETT: All science
builds on previous science, and science involves so many
different areas of expertise. This whole study is
a perfect example of the importance of
collaboration in science. JAMES BARRAT: More
than 40 patients, most of them
children, have taken part in RPE65 clinical trials
with excellent results. SPEAKER 2: Open the door,
and you did it, Robert. JAMES BARRAT: In 2017,
RPE65 gene therapy was recommended for approval
by a panel of the Food and Drug Administration for the treatment
of congenital Leber amaurosis. This success brings therapies
for other inherited diseases one step closer to reality. [MUSIC PLAYING] SPEAKER 2: You did it!


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