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PAST

(1960 – 2015) –Gene therapy seemed more like science fiction than actual science when the concept was introduced in the early 1970s. Today, however, there have been more than 2,600 completed gene therapy clinical trials. As gene therapies continue to provide hope for millions, here's a quick look at how we got here.

1972

The concept of gene therapy as a tool to treat genetic diseases is introduced to the world in a scientific paper for the first time.

The authors hypothesized that gene therapy may improve the management of human genetic diseases in the future, but they also urged caution until more can be learned.

Scientists start researching viral vectors, such as adenoviruses (common viruses that cause a range of illness) and retroviruses (viruses that use RNA as their genetic material), to determine how best to transfer genetic material to a host cell.

In 1984, a paper published by David Williams demonstrated that one could use a retrovirus to insert genes into blood-cell developing stem cells.

1980s

1990

Doctors are able to use a disabled virus to deliver genetic material to the cells of a rare disease patient.

W. French Anderson and his colleagues at the National Institutes of Health managed to deliver a gene called adenosine deaminase, or ADA, into the T-cells of a four-year-old girl born with a severe immunodeficiency disorder (SCID). Without ADA, the girl's T-cells died off quickly, preventing her from fighting off even minor infections. The gene transfer was a success, and the patient is now alive and active in the rare disorde community.

18-year-old Jesse Gelsinger dies after receiving an investigational adenovirus-based gene therapy while participating in a clinical trial at the University of Pennsylvania.

Gelsinger’s underlying rare disease was an X-linked genetic disease of the liver which left him unable to metabolize ammonia. As a result, gene therapy research grinds to a halt, and tighter regulatory controls to ensure safety are imposed for future trials.

1999

2003

The Human Genome Project concludes, providing researchers with a “map” of all genes found in human DNA.

The map of human genes, or genome, potentially allows scientists to pinpoint the genetic cause of different diseases and develop specially-tailored treatments for genetic diseases.

An NIH-funded clinical trial shows success in treating patients with a genetic blood disease called hemophilia B caused by alterations in the gene that codes for clotting factor IX (a protein produced naturally in the body which helps the blood form clots to stop bleeding).

Using a modified adeno-associated virus, scientists were able to package a normal factor IX gene into the virus and deliver it to the patient's liver cells — enabling the cells to produce factor IX themselves. This clinical trial marked the first time ever scientists were able to demonstrate success — giving hope to the premise that gene therapy could be a viable option for clotting disorders.

2011

PRESENT

(2015 – 2021) –Thanks to decades of research and safety protocols,recent clinical trials are demonstrating an an increasing number of gene therapies as safe and effective which may increase their chances of becoming a therapy. Potential applications of gene therapy are now more commonly considered for many patients with rare diseases. Here are some advancements in gene therapy to note.

EARLY 2016

The FDA officially approves a genetic treatment, or oligonucleotide therapy, called nusinersen, or Spinraza, for pediatric and adult patients with spinal muscular atrophy (SMA).
Spinraza, whilst not considered a gene therapy, is given as an infusion in the patient's spine over the course of several months, stimulates the body to produce survival motor neuron (SMN) protein that is lacking in patients with SMA. Once the body starts producing SMN protein, patients are able to preserve – and in some cases, even regain – muscle control that affects their walking, breathing, and swallowing, allowing for a longer life expectancy. With its approval in 2016, Spinraza becomes one of the very first FDA-approved genetic treatments in the US.

The FDA grants accelerated approval first Duchenne muscular dystrophy treatment for patients who have a confirmed genetic mutation in the dystrophin gene that can be treated by skipping exon 51, called Exondys 51.

The treatment, delivered by injection, allows the body to produce a slightly shorter form of the dystrophin protein that strengthens muscle fibers and protects them from injury – dystrophin is a protein that is deficient in people with DMD. Clinical studies show that Exondys 51 improves dystrophin levels in people with DMD and perhaps even slow the loss of muscle function measured by distance walked.

Pfizer is developing a mini-dystrophin gene therapy program in DMD, which is in Phase 3 testing. It is our hope that this will become yet another therapeutic option for patients with DMD in the near future.

LATE 2016

2018

Just four years after the “Ice Bucket Challenge,” a fundraising phenomenon that swept the globe with the intent to find a cure for the progressive genetic disorder amyotrophic lateral sclerosis (ALS), a new gene therapy is underway.

Using the funds raised from the challenge, scientists were able to devote more research to ALS and, in doing so, discovered five new genes connected to ALS and launched several clinical trials to test new treatments. In 2018, Pfizer announces a collaboration with Sangamo Therapeutics to explore a gene therapy approach designed to treat ALS patients associated with mutations in the C9ORF72 gene.

2020

At a virtual meeting of the European Hematology Association, researchers announce that three people with inherited blood disorders, including sickle cell disease and beta thalassaemia, a hemoglobin production disorder, were “functionally cured” with CRISPR technology in a clinical trial.

The study participants underwent a procedure where their bone marrow stem cells were harvested and then genetically edited to remove a mutation that caused their disease. After doctors transplanted the genetically modified cells back into the patients, they were able to avoid blood transfusions, which up until that point, had been the standard of care for their disease.

FUTURE

(2021 and Beyond) –The future for gene therapy is bright. In 2019, then-FDA commissioner Scott Gottlieb announced that, thanks to the incredible clinical success rate of gene therapies thus far, he expected the FDA to approve between 10 and 20 new gene therapies each year by 2025. Looking into the future, scientists are continuing to customize gene therapy and hopefully increase application in different genetic treatments. Here's what we have to look forward to:

GENE THERAPY TO PREVENT HEART DISEASE AND STROKE

In 2020, the founder and CEO of Verve Therapeutics announced that their research team was successfully able to use gene-editing (CRISPR) technology to edit the genes of 14 cynomolgus monkeys and lower the LDL (“bad”) cholesterol in the monkeys' blood.

After gene therapy, the monkeys' LDL levels plummeted by as much as 60 percent, while triglycerides dropped by as much as 65 percent. While it's still a long road before this treatment may be tested in human beings, researchers hope that lowering LDL and triglycerides by way of gene editing could potentially reduce heart disease, heart attack, and stroke in human beings.

A study published in May 2021 in the New England Journal of Medicine revealed a landmark approach to gene therapy.

In the trial, researchers collected blood-forming stem cells from children who were diagnosed with severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID. Using a new approach developed by a research team at UCLA, a new copy of the ADA gene was delivered into the stem cells by way of a viral vector. When the corrected stem cells were returned to the patient's body, they were able to produce a continual supply of healthy immune cells from there – as opposed to undergoing twice-weekly injections of the ADA enzyme indefinitely. Researchers think that this new treatment, if approved in the future, could become the standard of care for ADA-SCID, potentially offering an alternative in fighting the disease.

NEW APPROACHES TO TREAT SEVERE DISEASES

INCREASED ATTENTION, FUNDING FOR EXTREMELY RARE DISEASES

Because of the recent successes of gene therapy, patients with rare genetic disorders and their families are now lobbying more than ever to bring new possibilities to the forefront.

Case in point: Amber Freed, whose son Maxwell was diagnosed in 2018 with a genetic disorder so rare it didn't even have a name. Known as SLC6A1, the mutation of this particular gene causes movement and speech disorders, epilepsy, and developmental delays. Freed recently launched a fundraising campaign and a patient advocacy nonprofit for patients with the condition, increasing the known cases of the disorder from just 40 to more than 400. Also thanks to Freed's advocacy, researchers are now experimenting on mice with the SLC6A1 gene in the hopes that they can better understand the molecular basis of the disease and offer a future treatment. Trials and treatments for this disease and many other rare diseases are still years away, but the groundwork for gene therapies of the future is already being laid.

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