Category Archives: Gene therapy

Gene therapy may have the potential to fix or replace genetic mutations, which are changes in your DNA that affect how your body works.

Doctors use gene therapy, also called gene editing to directly alter your genes.

This approach may help treat diseases caused by a single mutation, such as beta-thalassemia or spinal muscular atrophy (SMA). Gene editing may also help treat certain cancers.

Gene editing tools such as CRISPR-Cas9 are very new and are rapidly changing. Researchers continue to study their full potential along with any risks they may pose.

Heres what experts know so far about gene therapy.

Genes are small segments of DNA that instruct your cells to make certain proteins when specific conditions are met.

Mutated genes, on the other hand, may cause your cells to make too much or too little of the necessary protein. Even small changes can have a domino effect across your body just as tiny changes in computer code can affect an entire program.

Gene therapy can address this issue by:

Scientists dont have tweezers small enough to edit your DNA by hand. Instead, they recruit a surprising ally to work on their behalf: viruses.

Typically, a virus would enter your cells and alter your DNA to create more copies of itself. But scientists can switch out this programming with their own, hijacking the virus to heal instead of harm. These vectors, as theyre called, dont have the parts they need to cause disease, so they cant make you sick the way a regular virus could.

There are two types of gene therapy:

Each type has its own benefits:

Gene therapy is different from genetic engineering, which means changing otherwise healthy DNA for the purpose of enhancing specific traits. Hypothetically, genetic engineering could potentially reduce a childs risk of certain diseases or change the color of their eyes. But the practice remains highly controversial since it hovers very close to eugenics.

Gene therapy may be used to treat a variety of genetic conditions, including:

When the RPE65 gene in your retinas doesnt work, your eyeballs cant convert light to electrical signals.

The gene therapy Luxturna, approved by the Food and Drug Administration (FDA) in 2017, can deliver a functional replacement of the RPE64 gene to your retinal cells.

The FDA-approved Hemgenix can treat the bleeding disorder hemophilia B. The viral vector instructs your liver cells to create more of the factor IX protein, which helps your blood clot.

Meanwhile, the gene therapy Zynteglo, approved by the FDA in 2022, treats beta-thalassemia by giving your bone marrow stem cells correct instructions for creating hemoglobin.

This blood disorder can lower the oxygen in your body because it decreases your bodys hemoglobin production.

In infantile-onset SMA, an infants body cant make enough of the survival of motor neuron (SMN) proteins necessary to build and repair motor neurons. Without these neurons, infants gradually lose their ability to move and breathe.

The gene therapy Zolgensma, approved by the FDA in 2019, replaces faulty SMN1 genes in an infants motor cells with genes that can create enough SMN proteins.

Your ABCD1 gene produces an enzyme that breaks down fatty acids in your brain. If you have cerebral adrenoleukodystrophy, this gene is either broken or missing.

Skysona, FDA approved as of 2022, delivers a functional ABCD1 gene so that fatty acids dont build up and cause brain damage.

The FDA has approved gene therapies to treat multiple types of cancer, such as non-Hodgkins lymphoma and multiple myeloma.

Most cancer gene therapies work indirectly by inserting new genes into a powerful antibody called a T cell. Your changed T cells can then latch on to cancerous cells and eliminate them, similar to how they attack viruses.

The therapy Adstiladrin, approved by the FDA in 2022, can treat nonmuscle-invasive bladder cancer by altering the DNA in your bladder cells themselves.

Some people considering gene therapy may feel uneasy about putting viruses in their body.

Keep in mind, though, that gene therapies undergo extensive testing before approval. The viruses in gene therapies are also fixed so they cant replicate similar to many vaccines.

That said, gene therapies may pose other risks:

Despite these issues, experts generally believe gene therapy offers more benefits than risks.

Most of the conditions treated with gene therapy are life threatening. The dangers of leaving them untreated often outweigh the risks of potential side effects.

Gene therapy does come with a few drawbacks that keep it from becoming a widespread treatment.

Gene therapy can only target certain mutations. This means it may not work for everyone with a specific condition.

For example, two people may have inherited vision loss. Currently, gene therapy can only treat vision loss caused by the RPE64 mutation.

Because gene therapy research is so new, experts do extensive safety testing before introducing their treatments to the public. It can take years to get FDA approval for each new therapy.

As you might imagine, gene therapies are expensive to manufacture and administer. This not only affects funding for clinical trials but also the price of the drug.

For example, the gene therapy Zolgensma is the most expensive drug in the United States at $2.1 million per dose. Even with insurance, that kind of price tag remains out of reach for the average American.

Scientists are trying to find ways to make the development process safer, cheaper, and more efficient so more people can access gene therapy.

Gene therapy works to treat several different genetic diseases by editing the mutations that cause them. As researchers further refine and expand this technology, they may find even more conditions that could be treated with it.

Experts are also continuing to explore options to make gene therapy more affordable so people who need these treatments have an easier time getting them.

Emily Swaim is a freelance health writer and editor who specializes in psychology. She has a BA in English from Kenyon College and an MFA in writing from California College of the Arts. In 2021, she received her Board of Editors in Life Sciences (BELS) certification. You can find more of her work on GoodTherapy, Verywell, Investopedia, Vox, and Insider. Find her on Twitter and LinkedIn.

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How Does Gene Therapy Work? Types, Uses, Safety - Healthline

Gene therapy is the product of man's quest to eliminate diseases. Gene therapy has three facets namely, gene silencing using siRNA, shRNA and miRNA, gene replacement where the desired gene in the form of plasmids and viral vectors, are directly administered and finally gene editing based therapy where mutations are modified using specific nucleases such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short tandem repeats (CRISPR)/CRISPR-associated protein (Cas)-associated nucleases. Transfer of gene is either through transformation where under specific conditions the gene is directly taken up by the bacterial cells, transduction where a bacteriophage is used to transfer the genetic material and lastly transfection that involves forceful delivery of gene using either viral or non-viral vectors. The non-viral transfection methods are subdivided into physical, chemical and biological. The physical methods include electroporation, biolistic, microinjection, laser, elevated temperature, ultrasound and hydrodynamic gene transfer. The chemical methods utilize calcium- phosphate, DAE-dextran, liposomes and nanoparticles for transfection. The biological methods are increasingly using viruses for gene transfer, these viruses could either integrate within the genome of the host cell conferring a stable gene expression, whereas few other non-integrating viruses are episomal and their expression is diluted proportional to the cell division. So far, gene therapy has been wielded in a plethora of diseases. However, coherent and innocuous delivery of genes is among the major hurdles in the use of this promising therapy. Hence this review aims to highlight the current options available for gene transfer along with the advantages and limitations of every method.

Keywords: Gene delivery; Gene therapy; Non-viral vectors; Transfection; Viral vectors.

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Gene therapy: Comprehensive overview and therapeutic applications

Thanks to collaboration between Stand Up Therapeutics and VectorBuilder, a paraplegic patient will get gene therapy for the first time  Business Standard

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Thanks to collaboration between Stand Up Therapeutics and VectorBuilder, a paraplegic patient will get gene therapy for the first time - Business...

gene editing, the ability to make highly specific changes in the DNA sequence of a living organism, essentially customizing its genetic makeup. Gene editing is performed using enzymes, particularly nucleases that have been engineered to target a specific DNA sequence, where they introduce cuts into the DNA strands, enabling the removal of existing DNA and the insertion of replacement DNA. Key among gene-editing technologies is a molecular tool known as CRISPR-Cas9, a powerful technology discovered in 2012 by American scientist Jennifer Doudna, French scientist Emmanuelle Charpentier, and colleagues and refined by American scientist Feng Zhang and colleagues. CRISPR-Cas9 functioned with precision, allowing researchers to remove and insert DNA in the desired locations.

The significant leap in gene-editing tools brought new urgency to long-standing discussions about the ethical and social implications surrounding the genetic engineering of humans. Many questions, such as whether genetic engineering should be used to treat human disease or to alter traits such as beauty or intelligence, had been asked in one form or another for decades. With the introduction of facile and efficient gene-editing technologies, particularly CRISPR-Cas9, however, those questions were no longer theoretical, and the answers to them stood to have very real impacts on medicine and society.

The idea of using gene editing to treat disease or alter traits dates to at least the 1950s and the discovery of the double-helix structure of DNA. In the mid-20th-century era of genetic discovery, researchers realized that the sequence of bases in DNA is passed (mostly) faithfully from parent to offspring and that small changes in the sequence can mean the difference between health and disease. Recognition of the latter led to the inescapable conjecture that with the identification of molecular mistakes that cause genetic diseases would come the means to fix those mistakes and thereby enable the prevention or reversal of disease. That notion was the fundamental idea behind gene therapy and from the 1980s was seen as a holy grail in molecular genetics.

The development of gene-editing technology for gene therapy, however, proved difficult. Much early progress focused not on correcting genetic mistakes in the DNA but rather on attempting to minimize their consequence by providing a functional copy of the mutated gene, either inserted into the genome or maintained as an extrachromosomal unit (outside the genome). While that approach was effective for some conditions, it was complicated and limited in scope.

In order to truly correct genetic mistakes, researchers needed to be able to create a double-stranded break in DNA at precisely the desired location in the more than three billion base pairs that constitute the human genome. Once created, the double-stranded break could be efficiently repaired by the cell using a template that directed replacement of the bad sequence with the good sequence. However, making the initial break at precisely the desired locationand nowhere elsewithin the genome was not easy.

Before the advent of CRISPR-Cas9, two approaches were used to make site-specific double-stranded breaks in DNA: one based on zinc finger nucleases (ZFNs) and the other based on transcription activator-like effector nucleases (TALENs). ZFNs are fusion proteins composed of DNA-binding domains that recognize and bind to specific three- to four-base-pair-long sequences. Conferring specificity to a nine-base-pair target sequence, for example, would require three ZFN domains fused in tandem. The desired arrangement of DNA-binding domains is also fused to a sequence that encodes one subunit of the bacterial nuclease Fok1. Facilitating a double-stranded cut at a specific site requires the engineering of two ZFN fusion proteinsone to bind on each side of the target site, on opposite DNA strands. When both ZFNs are bound, the Fok1 subunits, being in proximity, bind to each other to form an active dimer that cuts the target DNA on both strands.

TALEN fusion proteins are designed to bind to specific DNA sequences that flank a target site. But instead of using zinc finger domains, TALENs utilize DNA-binding domains derived from proteins from a group of plant pathogens. For technical reasons TALENs are easier to engineer than ZFNs, especially for longer recognition sites. Similar to ZFNs, TALENs encode a Fok1 domain fused to the engineered DNA-binding region, so, once the target site is bound on both sides, the dimerized Fok1 nuclease can introduce a double-stranded break at the desired DNA location.

Unlike ZFNs and TALENs, CRISPR-Cas9 uses RNA-DNA binding, rather than protein-DNA binding, to guide nuclease activity, which simplifies the design and enables application to a broad range of target sequences. CRISPR-Cas9 was derived from the adaptive immune systems of bacteria. The acronym CRISPR refers to clustered regularly interspaced short palindromic repeats, which are found in most bacterial genomes. Between the short palindromic repeats are stretches of sequence clearly derived from the genomes of bacterial pathogens. Older spacers are found at the distal end of the cluster, and newer spacers, representing more recently encountered pathogens, are found near the proximal end of the cluster.

Transcription of the CRISPR region results in the production of small guide RNAs that include hairpin formations from the palindromic repeats linked to sequences derived from the spacers, allowing each to attach to its corresponding target. The RNA-DNA heteroduplex formed then binds to a nuclease called Cas9 and directs it to catalyze the cleavage of double-stranded DNA at a position near the junction of the target-specific sequence and the palindromic repeat in the guide RNA. Because RNA-DNA heteroduplexes are stable and because designing an RNA sequence that binds specifically to a unique target DNA sequence requires only knowledge of the Watson-Crick base-pairing rules (adenine binds to thymine [or uracil in RNA], and cytosine binds to guanine), the CRISPR-Cas9 system was preferable to the fusion protein designs required for using ZFNs or TALENs.

A further technical advance came in 2015, when Zhang and colleagues reported the application of Cpf-1, rather than Cas9, as the nuclease paired with CRISPR to achieve gene editing. Cpf-1 is a microbial nuclease that offers potential advantages over Cas9, including requiring only one CRISPR guide RNA for specificity and making staggered (rather than blunt) double-stranded DNA cuts. The altered nuclease properties gave potentially greater control over the insertion of replacement DNA sequences than was possible with Cas9, at least in some circumstances. Researchers suspect that bacteria house other genome-editing proteins as well, the evolutionary diversity of which could prove valuable in further refining the precision and versatility of gene-editing technologies.

See more here:
Gene editing | Definition, History, & CRISPR-Cas9 | Britannica

As early as the 1960s, scientists speculated that DNA sequences could be introduced into patients cells to cure genetic disorders. In the early 1980s, David Williams, MD, and David Nathan, MD, at Boston Childrens Hospital published the first paper showing one could use a virus to insert genes into blood-forming stem cells. In 2003, the Human Genome Project wrapped up, giving us a complete blueprint of our DNA. In the past decade, gene therapy has become a reality for multiple diseases, especially those caused by mutations in a single gene.

Gene therapy falls into two main categories. Ex vivo gene therapy removes cells from the patient, introduces new genetic material, packaged in a delivery vehicle called a vector, then returns the cells to the patient. Boston Childrens is using this method for such disorders as sickle cell disease, adrenoleukodystrophy, chronic granulomatous disease and others. In vivo gene therapy involves direct IV infusion of the vector into the bloodstream or injection into a target organ like the eye. Boston Childrens uses in vivo gene therapy for several disorders, including hemophilia and ornithine transcarbamylase deficiency.

After a rocky start, gene therapy is on fire, drawing keen interest from the biopharmaceutical industry. And its still evolving and improving.

In 1990, 4-year-old Ashanthi de Silva became the first gene therapy success story. She was born with a severe combined immunodeficiency (SCID) due to lack of the enzyme adenosine deaminase (ADA). Without ADA, her T cells died off, leaving her unable to fight infections. Injections of a synthetic ADA enzyme helped, but only temporarily.

Doctors decided to deliver a healthy ADA gene into her blood cells, using a disabled virus that cannot spread in the body. Their success spurred more trials in the 1990s for the same form of SCID. Now in her 30s, de Silva is active in the rare disease community.

European researchers in the 1990s focused on SCID-X1, another form of SCID linked to the X chromosome. They reported the first cures in 2000, but within several years, five of the 20 treated children developed cancer.The viral vector that delivered the gene to their T cells had also activated an oncogene, triggering leukemia.

The U.S. saw another early setback: the 1999 death of 18-year-old Jesse Gelsinger, after receiving gene therapy for a rare metabolic disorder. In his case, the viral vector caused a fatal immune response.

Gene therapy came to a halt.

In the early 2010s, gene therapy experienced a renaissance. Scientists developed better viral vectors to deliver genetic therapies. They added regulatory elements called promoters and enhancers to direct the genes activity. These elements specified where and when the gene should turn on, and at what level. Investigators at Boston Childrens, in a global collaborative effort, led work that addressed the problem of leukemia, allowing gene therapy to resume for SCID-X1.

A REBIRTH IN BOSTON: GENE THERAPY TURNS 10

Born in 2010 with X-linkedsevere combined immunodeficiency(SCID-X1), Agustn spent the first few months of his life in isolation. He became the first patient to receive gene therapy at Boston Childrens and today is an active fifth-grade soccer and tennis player.

The new, modified vectors can more precisely target expression of genes in specific cell types, dont go astray in the body, and dont trigger the immune system. Some deliver genes meant to work for a short while and then inactivate themselves. Others carry genes that remain active long-term and pass to daughter cells as the cells divide. Popular viruses for gene therapy include adenoviruses, adeno-associated virus, and lentiviruses.

An example of an improved vector is the lentivirus vector used for sickle cell gene therapy at Boston Childrens. The vector silences a gene calledBCL11A, leading to production of fetal hemoglobin that is not affected by the sickle cell mutation. It was precision engineered to silence the gene only in precursors of red blood cells, a tweak that enabled the treated blood stem cells to live long-term in patients bone marrow. Williams led the vectors development, based on seminal research by Vijay Sankaran, MD, PhD, and Stuart Orkin, MD, in the Hematology/Oncology Program at Boston Childrens.

Traditional gene therapyuses viruses to carry healthy genes into cells, compensating for a faulty or missing gene. But the past decade has seen an explosion of other methods for delivering or fixing genes.

Gene editing uses various molecular tools that precisely target problematic genes and create a cut or break in their DNA. It can knock out a faulty gene, insert a new DNA sequence, or both in a cut and paste operation. The best-known gene editing systems are CRISPR/Cas 9, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs). The next generation of gene therapy for sickle cell disease is utilizing CRISPR to edit the BCL11A gene, based on work by Dan Bauer, MD, PhD, at Boston Childrens, then in Orkins laboratory.

Base editingis even more fine-tuned. It leverages the targeting ability of CRISPR, but relies on enzymes to chemically change one letter of a genes code at a time changing, say, C to T or A to G. These small changes can correct a spelling error mutation, silence a disease-causing gene, or help activate a specific gene. Unlike gene editing, base editing hasnt yet been tested in clinical trials, but it offers the promise of more precision, efficiency, and safety.Boston Childrens has several base editing projects on deck.

Other new approaches blur the line between gene therapy and drug treatment. For example, antisense oligonucleotides (ASOs) are drugs made up of short, synthetic pieces of DNA or RNA that target the messenger RNA made by the faulty gene. They prevent the gene from being translated into a bad protein or, in some cases, trick the cells machinery into making a good protein. Researchers can even customize ASOs to single patients. Tim Yu, MD, PhD, in the Division of Genetics and Genomics at Boston Childrens, has developed this approach to treat several very rare genetic conditions.

Another approach, RNA interference, uses small RNAs to silence a targeted gene by neutralizing the genes mRNA. (The lentivirus described above uses RNA interference to silence the BCL11A gene.)

Even the messenger RNAs used for some COVID-19 vaccines represent a form of gene therapy. The mRNAs introduce genetic code that cells then use to make the coronavirus spike protein, encouraging people to develop antibodies to the virus.

Today, ClinicalTrials.gov lists nearly 400 active gene therapy studies all over the world, and more than a dozen gene therapy drugs are on the market. At Boston Childrens, the Gene Therapy Program has more than 20 human trials completed or underway, with more in the pipeline. While gene therapies are currently expensive, its expected that prices will come down over time. And as a one-time treatment, gene therapy promises to save money in the long run by preventing a lifetime of illness a true revolution in medicine.

Learn more about the Gene Therapy Program at Boston Childrens Hospital

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A short history of gene therapy - Boston Children's Answers

The past twelve months have culminated in an unprecedented level of excitement, investment, and clinical progress within the gene therapy field. As the field strives to strike a delicate balance between safety and efficacy, in the context of increased regulatory scrutiny and safety challenges, attending the 4th Annual Gene Therapy Analytical Development as an analytical scientist has never been so important.

This years summit returns in-person to Boston to reunite 300+ analytical experts in innovative biotech, pharma and academia to continue to develop resilient, long-lasting and robust analytical tools to enhance the safety, quality and efficacy of gene therapy products.

Whether you are focusing on specific characterization methods, enhancing your genome sequencing, advancing your understanding of full and partial particles, or advancing your early-stage bioassays, with 4 tracks, 8 pre-conference workshops and a post-conference focus day, the 4th Gene Therapy Analytical Development Summit will encompass all aspects of analytical development, giving you the chance to address and overcome challenges.

If you work in quality control, quality assurance, or process development - weve listened and weve answered. This years agenda includes a novel track designed for quality control and process development groups working in gene therapy. Talks include enhancing the knowledge transfer between departments, bridging between analytical methods with regards to QC/PD, and enhancing in-process development support.

Whether you're working with AAV, non-viral vectors or lentiviral vectors, this is your opportunity to enhance your existing analytical methods and explore innovative new tools to support safe and effective gene therapy development.

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Gene Therapy Analytical Development Summit 2022 | Home

1. $3.5-Million Hemophilia Gene Therapy Is World's Most Expensive Drug  Scientific American
2. The Era of One-Shot, Multimillion-Dollar Genetic Cures Is Here  WIRED
3. The most expensive drug in the world: Hemgenix, a $3.5 million treatment for hemophilia B  EL PAS USA
4. 18-Year-Old Patient Says $3.5 Million Hemophilia Drug He Needs Seems a "Little Steep"  Futurism
5. View Full Coverage on Google News

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$3.5-Million Hemophilia Gene Therapy Is World's Most Expensive Drug - Scientific American

CAR T Global Consultant Inc. Announce their Collaboration with Titronbio - a company founded in Shanghai China by a renowned leader in the field of CAR T and Cell and Gene therapy  PR Newswire

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CAR T Global Consultant Inc. Announce their Collaboration with Titronbio - a company founded in Shanghai China by a renowned leader in the field of...

Cell and Gene Therapy Manufacturing Services Market Size In 2023 | Financial Performance, In-Depth Insight of Trends, Key Players (Thermo Fisher Scientific, Merck KGaA, Charles River Laboratories, Lonza), SWOT Analysis, Distributors/Traders List, Latest I  Digital Journal

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Cell and Gene Therapy Manufacturing Services Market Size In 2023 | Financial Performance, In-Depth Insight of Trends, Key Players (Thermo Fisher...

Espaol

The genes in your bodys cells play a key role in your health. Indeed, a defective gene or genes can make you sick.

Recognizing this, scientists have worked for decades on ways to modify genes or replace faulty genes with healthy ones to treat, cure, or prevent a disease or medical condition.

This research is paying off, as advancements in science and technology today are changing the way we define disease, develop drugs, and prescribe treatments.

The U.S. Food and Drug Administration has approved multiple gene therapy products for cancer and rare disease indications.

Genes and cells are intimately related. Within the cells of our bodies, there are thousands of genes that provide the information to produce specific proteins that help make up the cells. Cells are the basic building blocks of all living things; the human body is composed of trillions of them.

The genes provide the information that makes different cells do different things. Groups of many cells make up the tissues and organs of the body, including muscles, bones, and blood. The tissues and organs in turn support all our bodys functions.

Sometimes the whole or part of a gene is defective or missing from birth. This is typically referred to as a genetically inherited mutation.

In addition, healthy genes can change (mutate) over the course of our lives. These acquired mutations can be caused by environmental exposures. The good news is that most of these genetic changes (mutations) do not cause disease. But some inherited and acquired mutations can cause developmental disorders, neurological diseases, and cancer.

Depending on what is wrong, scientists can do one of several things in gene therapy:

To insert new genes directly into cells, scientists use a vehicle called a vector. Vectors are genetically engineered to deliver the necessary genes for treating the disease.

Vectors need to be able to efficiently deliver genetic material into cells, and there are different kinds of vectors. Viruses are currently the most commonly used vectors in gene therapies because they have a natural ability to deliver genetic material into cells. Before a virus can be used to carry therapeutic genes into human cells, it is modified to remove its ability to cause infectious disease.

Gene therapy can be used to modify cells inside or outside the body.When a gene therapy is used to modify cells inside the body, a doctor will inject the vector carrying the gene directly into the patient.

When gene therapy is used to modify cells outside the body, doctors take blood, bone marrow, or another tissue, and separate out specific cell types in the lab. The vector containing the desired gene is introduced into these cells. The cells are later injected into the patient, where the new gene is used to produce the desired effect.

Before a gene therapy can be marketed for use in humans, the product must be tested in clinical studies for safety and effectiveness so FDA scientists can consider whether the risks of the therapy are acceptable considering the potential benefits.

The scientific field for gene therapy products is fast-paced and rapidly evolving ushering in a new approach to the treatment of vision loss, cancer, and other serious and rare diseases. As scientists continue to make great strides in this therapy, the FDA is committed to helping speed up development by interacting with those developing products and through prompt review of groundbreaking treatments that have the potential to save lives.

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How Gene Therapy Can Cure or Treat Diseases | FDA