Gene therapy now used to treat diseases ranging from neuromuscular disorders to cancer to blindness,
despite repeated setbacks before the turn of the century.
However, success is frequently conditional.
Some of these treatments help treat disease,
but they come with a hefty price tag and other barriers to access:
Even if patients are aware that a procedure for their disease exists,
and even if they can afford it or have insurance that would pay the cost,
which can range from $400,000 to $2 million,
they may not be able to go to one of the few academic facilities that offer it.
Other treatments reduce symptoms but do not address the underlying reason.
“Completely healing patients is going to be a great achievement,” says Julie Crudele,
a neurologist and gene therapy researcher at the University of Washington.
“But it’s not [yet] an achievable goal in a lot of instances.”
Even little steps forward set the way for future improvement,
she argues, citing findings with her Duchenne muscular dystrophy patients:
“We learn vital things in the majority of these clinical trials.”
Gene therapy researchers can now point to a growing list of successful gene therapies thanks to new information and persistent research.
PREVENTING VISION LOSS WITH GENE SWAPS
Some newborns are born with significant visual loss due to retinal illnesses that,
in the past, would have resulted in utter blindness.
Some of them are now able to benefit from a gene therapy developed by Jean Bennett and Albert Maguire,
a husband-and-wife duo who are now ophthalmologists at the University of Pennsylvania.
None of the genes now known to cause vision loss and blindness
were discovered when the couple started researching retinal illness in 1991.
RPE65, a possible target gene discovered in 1993 by researchers.
Bennett and Maguire tested a medication targeting that gene in three dogs
with severe visual loss seven years later, and restore all three pups’ vision.
In humans, Leber’s congenital amaurosis is the genetic disorder that most closely matches the dogs’ visual loss (LCA).
When a photon impacts the retina, a layer of light-sensitive cells in the rear of the eye,
LCA stops the retina from correctly reacting or sending messages to the brain.
The disorder can induce uncontrollable eye shaking (nystagmus),
prevent pupils from responding to light, and lead to permanent blindness by the age of 40.
The condition has been related to mutations or deletions in any of 27 genes
involved in retinal development and function, according to researchers.
There was no cure before gene therapy.
RPE65 mutations are only one cause of hereditary retinal degeneration,
but it was one that Bennett and Maguire could do anything about.
The researchers injected a harmless adeno-associated virus (AAV) into a patient’s eye right beneath the retina,
which they programmed to find retinal cells and install a healthy version of the gene.
The Food and Drug Administration approved voretigene neparvovecrzyl (marketed as Luxturna)
in 2017 for the treatment of any heritable retinal dystrophy caused by a mutated RPE65 gene,
including LCA type 2 and retinitis pigmentosa, another congenital eye disease
that affects photoreceptors in the retina following a series of clinical trials.
Luxturna was the first FDA-approved in vivo gene therapy,
which is a type of gene therapy that is administered to target cells inside the body
(previously approved ex vivo therapies deliver the genetic material to target cells in samples collected from the body, which then reinjected).
Luxturna’s manufacturer, Spark Therapeutics,
estimates that about 6,000 people worldwide and between 1,000 and 2,000 in the United States may be eligible for treatment,
a small enough number that the FDA granted Luxturna “orphan drug” status,
a designation that encourages the development of treatments for rare diseases.
That wasn’t enough to lower the price.
The treatment costs around $425,000 for each injection,
or roughly $1 million if both eyes needs treatment.
“I have not yet seen anybody in the United States who hasn’t obtained access based on inability to pay,” Maguire says, despite the cost.
Those who have been treated have seen tremendous improvements:
patients previously unable to see well have had their vision returned, frequently rapidly.
Some others claimed that after receiving the injections, they were able to see stars for the first time.
While it’s uncertain how long the improvements will persist,
follow-up data from a phase 3 trial published in 2017 indicated that all 20 patients
who received Luxturna had maintained their enhanced vision three years later.
Bennett claims that a five-year follow-up study with 29 patients,
which is presently being peer-reviewed, yielded comparable positive outcomes.
“These people can now achieve things they could never have imagined, and they’re more self-sufficient and enjoying life.”
INSTRUCTION FOR THE IMMUNE SYSTEM IN THE FIGHT AGAINST CANCER
Gene therapy has also made progress against cancer.
Chimeric antigen receptor (CAR) T cell treatment instructs a patient’s immune cells to recognize and target malignant cells.
Steven Rosenberg the National Cancer Institute’s chief of surgery,
assisted in the development of the therapy and published the first successful results in a 2010 research for lymphoma treatment.
“That patient had tremendous amounts of illness in his chest and belly,
and he had a complete regression,” Rosenberg adds, adding that the decline has now lasted 11 years.
CAR T cell treatment uses T cells, which are white blood cells that act as the first line of defense against infections.
The method employs a patient’s T cells, which extract and are genetically modified to produce cancer-specific receptors.
The changed T cells, which now can recognize and fight malignant cells,
proliferate and remain on the lookout for future encounters after being pumped back into the patient.
The results of a CAR T cell treatment termed tisagenlecleucel for acute lymphoblastic leukemia (ALL),
one of the most frequent childhood malignancies published in 2016 by researchers at the University of Pennsylvania.
Mutations in the DNA of bone marrow cells cause huge amounts of lymphoblasts,
or undeveloped white blood cells, to amass in the bloodstream in ALL patients.
Adults have a limited chance to cure, and fewer than half live more than five years after diagnosis.
When used to treat ALL, CAR T cells incredible effective—one modified T cell can kill up to 100,000 lymphoblasts.
In the University of Pennsylvania research, 29 of 52 ALL patients who treat with tisagenlecleucel achieved long-term remission.
The FDA approved the therapy (marketed by Novartis as Kymriah) for treating ALL based on the findings of that trial,
and the agency approved it for treating diffuse large B cell lymphoma the following year.
The one-time surgery can cost up to $475,000.
The use of CAR T cells is not without risk.
It can have serious adverse effects, such as cytokine release syndrome (CRS),
a hazardous inflammatory response that can vary from mild flu-like symptoms to multiorgan failure and even death in the most severe cases.
CRS isn’t just a side effect of CAR T therapy: It was first noticed as a side effect of antibody treatments used in organ transplants in the 1990s.
Doctors now know how far they may push treatment without developing CRS because of a mix of improved medications and increased attention.
“We know how to deal with side effects as soon as they arise,” Rosenberg says,
“and serious disease and death from cytokine release syndrome have declined dramatically since the early days.”
The remission rate for ALL patients treated with Kymriah was around 85 percent by 2020.
After a year, more than half of the participants had no relapses.
Novartis intends to track the outcomes of all patients
who received the medication over the next 15 years to better understand how long it lasts.
BLOOD DISORDERS PRECISION EDITING
In vivo gene editing using a system called CRISPR has become one of the most promising gene therapies
since Jennifer Doudna and Emmanuelle Charpentier discovered it in 2012,
a feat for which they shared the 2020 Nobel Prize in Chemistry,
This past June, the initial results published of a modest clinical trial targeted at treating sickle cell disease
and a closely related ailment known as beta-thalassemia.
Millions of people worldwide suffer from sickle cell disease,
which causes the development of crescent-shaped red blood cells
that are stickier and more rigid than healthy cells,
resulting in anemia and life-threatening health problems.
Millions more affected with beta-thalassemia,
which made by a separate mutation that causes the body to generate less haemoglobin,
the iron-rich protein that allows red blood cells to carry oxygen.
Bone marrow transplants may provide a cure for those who can identify matching donors,
but otherwise, blood transfusions and drugs to treat accompanying problems are the mainstays of treatment for both diseases.
Because sickle cell disease and beta-thalassemia made by single-gene mutations,
they are good candidates for gene-editing therapy.
The CRISPR-Cas9 approach edits the patient’s genome using DNA sequences from bacteria
(clustered regularly interspaced short palindromic repeats, or CRISPR) and a CRISPR-associated enzyme (Cas for short).
CRISPR sequences transcribe into RNA,
which locates and identifies DNA sequences that are responsible for a certain disease.
Transcribed RNA locates the target sequence when packed with Cas9,
and Cas9 snips it out of the DNA, fixing or deactivating the faulty gene.
Vertex Pharmaceuticals and CRISPR Therapeutics presented unpublished results
from a clinical trial of beta-thalassemia and sickle cell patients treated with CTX001,
a CRISPR-Cas9-based therapy, at a conference this past June.
In both situations, the therapy provides a gene that stimulates the production of good fetal hemoglobin,
a gene that ordinary turned off shortly after birth rather than shutting down a target gene.
After three months or more of treatment with CTX001,
all 15 persons with beta-thalassemia had significantly increased hemoglobin levels and no longer required blood transfusions.
Seven persons with severe sickle cell disease take the same medication,
and all of them had raised hemoglobin levels and reported being pain-free for at least three months.
Five participants with beta-thalassemia and two with sickle cell disease showed benefits that lasted more than a year.
Patients are still being enrolled in the trial, which is still ongoing.
According to a Vertex spokeswoman, the company plans to enroll 45 patients in total
and petition for FDA approval in the United States as early as 2022.
SUSPENDING A POTENTIALLY DEADLY ILLNESS
Motor neurons—the nerves that control muscle movement and connect the spinal cord to muscles and organs—degrade, malfunction,
and die in spinal muscular atrophy (SMA), a neurodegenerative illness.
It is commonly detected in newborns and toddlers.
The underlying cause is a genetic defect that prevents the generation of a protein necessary
for the construction and maintenance of motor neurons.
SMA is classified into four kinds based on the severity of the disease
and the amount of motor neuron protein that a person’s cells may still make.
Even the most fundamental tasks, such as breathing, sitting,
and swallowing, become extremely difficult in the most severe or type I cases.
In the past, babies diagnosed with type I SMA had a 90 percent fatality rate after one year.
Adrian Krainer, a biochemist at Cold Spring Harbor Laboratory,
became interested in SMA after attending a symposium sponsored by the National Institutes of Health in 1999.
Krainer was researching how RNA mutations create cancer and genetic illnesses by disrupting a process called splicing,
and researchers hypothesized that a flaw in the process could be the cause of SMA.
After RNA transcribe from a DNA template, it must edit or “spliced” into messenger RNA (mRNA) before it can direct the production of proteins.
Some sequences (introns) are removed during the editing process,
while those that remain (exons) are connected.
Krainer noticed parallels between the problems associated with SMA
and one of the mechanisms he was researching—namely,
a splicing error in which an essential exon delete by accident during RNA splicing.
One of these critical gene sequences, named SMN1, was absent in people with SMA.
“If we can figure out why this exon is being skipped and discover a remedy for it,” Krainer says,
“then perhaps this will assist all [SMA] sufferers.”
Antisense therapy, which he and his team devised,
uses single strands of synthetic nucleotides to convey genetic instructions directly to body cells [see “The Gene Fix”].
In the case of SMA, the instructions cause a different motor neuron gene, SMN2,
to create far more of the missing motor neuron protein than it typically does, essentially filling in for SMN1.
The first clinical trial to assess the method began in 2010,
and nusinersen was authorized by the FDA in 2016.
(marketed as Spinraza).
Because the treatment does not integrate into the genome,
it must give every four months to keep protein production going.
It’s also prohibitively expensive: a single Spinraza treatment can cost up to $750,000 in the first year and $375,000 every year after that.
It used to treat over 10,000 individuals around the world since 2016.
Spinraza can enable children with any of the four forms of SMA to live longer and more active lives,
even if it doesn’t restore normal motor function (a single motor neuron gene can’t make enough protein for that).
Spinraza has improved patients’ motor function in many situations,
allowing even the most severely affected individuals to breathe, swallow, and sit upright on their own.
“The most spectacular effects are in patients who are treated very soon after birth when they receive a genetic diagnosis from newborn screening,” adds Krainer.
“Then you can prevent the disease from starting—for several years, if not permanently.”