Gene Therapy: A New-Generation Approach for CRISPR, SMA, and Cancer Treatment

Gene therapy is a technique that uses genes to treat, prevent, or cure a disease or medical disorder. Often, gene therapy works by adding new copies of a damaged gene or by replacing a defective or missing gene in a patient's cells with a healthy version of that gene. Human gene therapy aims to modify or manipulate the expression of a gene or alter the biological characteristics of living cells. In this way, gene therapy aims to treat diseases by altering the genes of humans, and it is done in three main ways:

Replacing a disease-causing gene with a healthy copy of the gene

Deactivating a malfunctioning, disease-causing gene

Introducing a new or modified gene into the body to help treat a disease.

Gene therapy products aim to treat a variety of diseases, including cancer, genetic disorders, and infectious diseases. Gene therapy products are diverse, primarily including: circular DNA molecules (plasmid DNAs) designed to carry therapeutic genes into human cells; viruses (viral vectors (viral carriers)) or bacteria (bacterial vectors (bacterial carriers)) that have the ability to carry genetic material into human cells after losing their infectious disease-causing properties; human gene editing technology aimed at carrying therapeutic genes, disrupting harmful genes, and repairing mutated genes; and patient-derived cellular gene therapy products, which are taken from the patient, and genetically modified (usually using a viral vector) and then returned to the patient.

Gene therapies, primarily performed through three methods – gene insertion, silencing (suppression), and editing – yield the best results, particularly in genetic disorders caused by changes in a single gene. Approved gene therapies for the various disorders include: cerebral adrenoleukodystrophy, inherited blood disorders such as sickle cell anemia, thalassemia, and hemophilia, inherited neuromuscular diseases such as Duchenne muscular dystrophy and spinal muscular atrophy (SMA), and inherited retinal (eye) diseases such as Leber's congenital amaurosis and metachromatic leukodystrophy.

In addition to these diseases, scientists are also researching gene therapy for the treatment of HIV and cancer, as well as many other genetic disorders.

In addition, clinical trials of gene therapy in humans have been helpful in treating a variety of diseases and disorders, including severe combined immunodeficiency, hemophilia and other blood disorders, blindness caused by retinitis pigmentosa, leukemia, inherited neurological disorders, cancer, cardiovascular diseases, and infectious diseases. It has been stated that gene therapy can treat various genetic and hereditary diseases using both viral and non-viral vectors (carriers), and preclinical and clinical studies conducted with gene therapy for the treatment of various diseases such as cystic fibrosis, diabetes, and some cancers have shown promising results.

Examples of gene therapies approved in the U.S.:

Casgevy™ (exagamglogene autotemcel) is an approved, one-time CRISPR/Cas9 gene editing therapy for patients 12 years and older with severe sickle cell anemia (SCA) or transfusion-dependent beta-thalassemia.

Elevidys® (delandistrogene moxeparvovec-rokl) is an approved, one-time gene therapy to treat ambulatory people who are 4 years and older with Duchenne muscular dystrophy (DMD) and a confirmed mutation in the dystrophin gene mutation.

Hemgenix® (etranacogene dezaparvovec-drlb) is an FDA-approved, one-time gene therapy for adults with hemophilia B, a rare genetic bleeding disorder.

Lenmeldy (atidarsagene autotemcel) is a one-time, incurative gene therapy approved by the FDA in 2024 to treat children with pre-symptomatic late infantile, pre-symptomatic early juvenile and early symptomatic early juvenile, referred to as early-onset, metachromatic leukodystrophy (MLD).

Luxturna® (voretigene neparvovec-rzyl) is an approved one-time gene therapy for the treatment of children and adults diagnosed with biallelic RPE65 mutation-associated retinal dystrophy, a rare genetic disorder that causes vision loss.

Lyfgenia™ (lovotibeglogene autotemcel) is an FDA-approved one-time gene therapy for patients 12 years and older with a history of sickle cell anemia (SCA) and vaso-occlusion events (VOE).

Roctavian™ (valoctocogene roxaparvovec-rvox) is an approved one-time gene therapy for adults with severe hemophilia A, a bleeding disorder caused by clotting factor VIII deficiency, who do not have antibodies to the virus, AAV5.

Skysona® (elivaldogene autotemcel) is a one-time gene therapy approved to slow the progression of neurological dysfunction in boys aged 4 to 17 years diagnosed with early-stage active cerebral adrenoleukodystrophy (CALD).

Zolgensma® (onasemnogene abeparvovec) is a one-time gene therapy used to treat Spinal Muscular Atrophy (SMA) in children under 2 years of age, particularly those with double allele mutations in the SMN1 gene.

Zynteglo^TM (betibeglogene autotemcel) is a one-time, personalized gene therapy developed by bluebird bio for the treatment of require regular red blood cell (RBC) transfusions beta-thalassemia (TDBT) in adults, adolescents, and children.

Like any treatment, gene therapy can have both benefits and drawbacks. The main benefits of gene therapy include: providing a new treatment for a disease for which there are no other treatment options; the fact that a single application is sufficient compared to treatments requiring continuous therapy and application; preventing devastating consequences in later stages of the disease by receiving gene therapy in the early stages; and treating the cause of the disease, not just its symptoms. Looking at the negative aspects of gene therapy, we can see that it may not be accessible to everyone due to cost, access to technology, and other factors; as with any treatment, there are side effects associated with gene therapy (especially immune system reactions (e.g., even when viruses used as carriers are in forms that have lost their infectious properties, the patient's immune system may still react to them, sometimes leading to serious reactions)); and the need for chemotherapy or other preparatory treatments before gene therapy, which can cause unwanted side effects and be time-consuming. When a patient is deemed suitable for gene therapy by his/her physician, what the patient does during gene therapy depends on the type of treatment he/she receives. Gene therapy is administered intravenously (i.v.) directly into a vein. Gene therapy is generally administered only once, unlike other treatments.

To prepare for treatment, the patient may need genetic testing to confirm he/she has a specific gene mutation, blood tests, chemotherapy or other treatments, and blood draws or bone marrow procedures to obtain stem cells for gene therapy.

According to current references, long-term follow-up after gene therapy is crucial for understanding the durability and safety of gene therapies; and robust follow-up protocols and databases will help improving the treatments. Finally, it is stated that gene therapy will likely be integrated with other treatment methods such as drug therapy (pharmacotherapy), cell therapy, and immunotherapy (treatment through immune system regulation) to create comprehensive and personalized treatment plans, thus improving treatment outcomes and providing holistic patient care.

While gene therapy aims to improve the success rate of many serious diseases that cannot be treated with traditional therapies, it also faces some challenges, as is the case with many new and advanced technological treatments. The main challenges include ensuring the safe transfer of genetic material to patients' cells, targeting the correct cells or genes, and minimizing the risk of side effects. In addition, the cost of treatment and insurance coverage can also be barriers.

In particular, in this new treatment method, recent rapid advancements in biotechnology and genetic engineering, including CRISPR-Cas9, base editing, CAR T-cell therapy, and improved vector modifications, have significantly increased the precision and efficiency of gene transfer methods.

The “immune system response”, which can be defined as a major safety issue in gene therapy, is also vital for improving the safety of gene therapy, as advances in understanding inflammatory responses and gene transfer mutations help identify and mitigate immune reactions that may occur during treatment, thus improving patient outcomes. Reducing the costs of these treatments is also of great importance, particularly in facilitating access to them for middle and low-income countries.

In addition to this information, current scientific sources indicate that ethical and regulatory challenges related to studies on germ cell (reproductive cell) editing will require international consensus, responsible research, and public participation.

Since the concept of gene therapy was introduced approximately 50 years ago, more than two dozen gene therapies have received clinical use approval from drug regulatory agencies in different countries, and successful results have been achieved in various fields, including SMA and hematological (blood cell-affecting) cancers. However, gene therapies are quite expensive, new, and high-tech products, which can hinder patients' access to necessary treatment. Furthermore, treatment safety has always been a crucial issue requiring a benefit/risk assessment since the initial discovery of this treatment method, and research in gene therapy-related safety has been enhanced by rapid progress (e.g., developments such as the use of non-integrated vectors or even naked DNA). However, it is noted that germline gene therapy (GGT) (which involves modifying cell nuclei inherited from generation to generation), still has significant unresolved safety issues, and there is a broad consensus in the scientific community that GGT should not be introduced into clinical use until these efficacy and safety issues are resolved. In our country, research on gene therapy has been intensified, especially in recent years, and successful and promising results have been obtained. Although the current gene therapy products available on the market worldwide are limited, gene therapy research continues to seek new and effective treatments for various diseases.