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The prospects of gene therapy are both exciting and frightening. Studies of its use for numerous diseases are currently underway. By altering the genetics of human cells, gene therapy offers reason to hope for cures to some of mankind’s most pestilent maladies. This promising potential is tempered by some significant concerns, however. Potential risks of genetic damage, immune system activation, and misuse are very real. You have every right to be interested in this topic, and as with any polarizing issue, it is best to be well-informed.
What is gene therapy?
In the broadest terms, gene therapy adds a new gene where the current one is missing or mutated, edits a gene to produce more advantageous functions, or silences a gene to reduce the negative effects of its presence. Genes are the code that our cells use as an instruction manual to function and produce certain proteins. Gene mutations or missing instructions can result in terrible ramifications, which could be righted by adjusting the genetic code or stifling its expression. Alternatively, a cell type’s genetics could be changed to put them to use in fighting a disease like cancer. The cells whose genes are altered could be autologous, meaning they are the patient’s cells or could be allogeneic cells from a donor.
Types of gene therapy
Besides the source of cells being a variable to consider, the type of cell is another matter that can differ within the field of gene therapy. Body tissues consist of what are called “somatic cells” that perform different functions within the organs that they reside in. Germline cells, in comparison, exist within eggs and sperm, and they differentiate into different body cell types to form the fetus. Gene therapy can involve either somatic or germline cells.
Regardless of whether a germline or somatic cell is targeted with gene therapy, you have to get the corrected genetic code into the cell. Vectors handle the delivery of new genetic material to the proper cells. Most commonly, vectors are a weakened form or part of a virus. You did indeed read that correctly. The same types of organisms that plague us with the common cold and other infectious diseases can be recruited and altered to be the shipping and handling agents for gene therapy. They are quite adept at inserting themselves into cells’ genetic material. Adenoviruses and retroviruses are two commonly used types of viral vectors.
The vector can deliver the genetic material by being infused intravenously, or cells can be removed from the patient in order for the vector to be applied ex vivo (outside of the body). For instance, Lentiglobin is a gene therapy product that is used for sickle cell disease. It is applied to a sickle cell patient’s hematopoietic stem cells ex vivo. When the cells, complete with their newly added beta-globin gene, are infused back into the patient with sickle cell anemia, they begin producing blood cells with normal hemoglobin, helping to avoid complications from red blood cell deformation.
While a viral vector can deliver new genetic material to a cell, it can alternatively be used to haul enzymes used to cut and repair genetic material. This process is called “gene editing” to differentiate it from other types of gene therapy. CRISPR is a well-known example of a gene editing technique.
Gene therapy techniques
Using technology such as CRISPR, a faulty gene in a cell can be cut out, and a new sequence of code can be inserted. This amounts to gene replacement. On the other hand, instead of replacing a gene, similar technologies can be used to conduct faulty gene repair in which the coding sequence is adjusted to lead to a change in cellular function. Either way, the objective is to alter a cell’s DNA to enable it to work in an advantageous manner. As the new and improved cell divides, its progeny would carry the replaced or repaired DNA code too.
Alternatives to editing the existing code include gene addition and gene silencing. With gene addition, a vector is used for gene transfer to a cell’s nucleus and into its DNA. The added gene is intended to get the cell functioning better. Conversely, existing genes can be silenced, resulting in the cell not being able to produce problematic proteins. Gene silencing does not involve changing the genetic code, but rather, it consists of using interfering RNA or adding chemical structures to the cell’s DNA to render it unusable.
Benefits of gene therapy techniques
The nuts and bolts of gene therapy are fascinating, but the potential health outcomes from altering cellular function are what fuel our excitement about this approach. Many of the studies regarding gene therapy for particular diseases have not left the laboratory stage yet. Other studies are ongoing at the clinical stage of testing techniques on people. Far fewer of the methods have progressed to the point of Food and Drug Administration (FDA) approval and use for treatment currently.
Neurological Disorders
Parkinson’s Disease
The genetic makeup of Parkinson’s disease is variable from one patient to another, and in fact, over 40 different genes have been implicated as potential contributors. Regardless of the specific gene abnormality, the result is reduced production of the neurotransmitter dopamine and consequent central nervous system dysfunction. Symptoms mainly involve tremors and impaired movement. Traditionally, treatment involves supplying dopamine with medication like Sinemet (carbidopa/levodopa) or dopamine agonists like ropinirole.
Gene therapy using adeno-associated viruses is the subject of intense research currently. One example of a gene abnormality that contributes to Parkinson’s disease is a mutation in the GBA1 gene, and gene editing to replace the mutation with a normal GBA1 gene is the subject of a clinical trial.
Alzheimer’s Disease
A better understanding of the human genome and the pathology of Alzheimer’s disease has led to a fervor for treating it with gene therapy. Unfortunately, these efforts are still at the early stages. One such focus has been on using a viral vector to transfer a nerve growth factor gene that may help certain brain cells to survive and offset the lack of the neurotransmitter acetylcholine in Alzheimer’s disease.
One of the challenges with trying to conduct effective gene therapy for neurodegenerative diseases like Parkinson’s and Alzheimer’s is getting the helpful gene into enough of the somatic brain cells because these cells are not dividing and passing along the new material. The vector must be very efficient. Until these obstacles are overcome, doctors who treat Alzheimer’s will still largely rely on medications like Aricept (donepezil) and Namenda (memantine).
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a devastating genetic disease that can affect anyone from newborns to adults, causing weakness and low muscle tone. The resultant muscle atrophy can be severe enough to cause ineffective breathing, and in some types of SMA, death is common before age 2. Most often, the disease is related to mutated survival motor neuron 1 (SMN1) gene, leading to less SMN1 protein and making the individual reliant on survival motor neuron 2 (SMN2) gene expression for SMN2 proteins.
The more copies of the SMN2 gene that an individual with SMA has, the better off they are. Nursineran and risdiplam are two FDA-approved drugs that modify the expression of the SMN2 gene to permit more of its protein production.
In 2019, the FDA approved onasemnogene abeparvovec, a gene replacement therapy for SMA, for use in patients less than 2 years of age. Using a viral vector administered in a one-time intravenous dose, the treatment replaces the defective gene for SMN1 with a normal one. Survival and other outcome measures have been markedly better in studies. The cost of a dose has been estimated to be over $2 million.
Single-gene genetic disorders
Cystic Fibrosis
For over 30 years now, human gene therapy has been of interest for the treatment of cystic fibrosis, a lung disease characterized by the accumulation of thick airway mucus due to a genetic mutation in chloride channel production. The gene has been named the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Unfortunately, numerous different mutations in the CFTR gene exist, making it difficult to find a curative gene therapy for all those with the disease, but gene therapy research efforts continue. In the meantime, small molecule therapies like lumacaftor-ivacaftor have provided a workaround to help cells establish functional CFTR proteins.
Hemophilia
Hemophilia results in excessive bleeding due to a deficiency in clotting factors, proteins that circulate in the bloodstream and work together to form a blood clot when necessary. The deficiency is either in the gene responsible for clotting factor VIII (hemophilia A) or clotting factor IX (hemophilia B) production. Since these factors are in our circulation, inserting a normal gene into any cells with access to the bloodstream can lead to higher clotting factor levels. Hemgenix (etranacogene dexaparvovec-drib) is an FDA-approved gene therapy that targets liver cells to provide a normal factor IX gene. The cells are then able to manufacture factor IX, release it into the bloodstream, and allow a patient with hemophilia B to form blood clots more normally.
Muscular dystrophy
The Duchenne muscular dystrophy (DMD) gene is a lengthy bit of genetic code, so there is a lot of room for error. Mutations in the gene cause DMD due to a lack of dystrophin, a protein that muscle cells require. The resultant progressive muscle weakness eventually leads to an inability to walk or breath. In June 2023, the FDA approved Elevidys (delandistrogene moxeparvovec), a gene therapy that uses an adeno-associated virus vector to insert a gene that codes for micro-dystrophin production. With micro-dystrophin being produced in muscles, the hope is that DMD patients will have better outcomes.
Cancer
Leukemia
Gene therapy for cancer can look a bit different than the aforementioned examples. Our immune system is capable of killing cancer cells; in fact, it is our natural surveillance system to prevent cancer. Scientists have discovered ways to enhance and target cells of our immune system for cancer treatment. Chimeric antigen receptor T (CAR-T) cells are T cells that have been genetically altered to attack cancer. To do so, a cancer patient’s T cells are harvested from their bloodstream, genetically modified to produce a receptor that attaches to and kills a cancer cell, and infused back into the patient. Tisagenlecleucel and brexucatagene are two FDA-approved CAR-T therapies for B-cell acute lymphoblastic leukemia. The CAR-T cells with these gene therapies target the cancerous B cells.
Lymphoma
CAR-T cells can also be directed to attack lymphoma cells. The FDA has approved three different CAR-T products for treatment of diffuse large B cell lymphoma, lisocabtagene maraluece, axicabtagene ciloleucel, tisagenlecleucal.
Tumors
Our immune system can be pointed to tumor cells in other ways. For instance, Adstiladrin (nadofaragene firadenovec) has FDA approval for in-vivo (inside the body) treatment of bladder cancer. The drug is instilled into the patient’s bladder, where an adenovirus vector delivers an interferon gene to bladder cells. Production of the interferon heightens the immune system’s fight against bladder cancer.
Ethical and social considerations of gene therapy techniques
Progress with moving gene therapy from the lab to a useful medical treatment has been slower than desired, but things are accelerating with new gene editing technology. The research and development of these therapies is costly. Consequently, the end product costs can be staggering, with the range extending over $1 million at times. This issue raises concern that not everyone who could benefit from gene therapy will have access to it. The social and ethical questions surrounding gene therapy merely start with cost.
Germline gene therapy, which alters the genetics of an egg or sperm, prompts the most controversy. Ethical concerns include how truly informed consent can be achieved. More striking are the worries about using germline gene therapy for enhancement rather than disease treatment or prevention. A troubling, theoretical example would be altering the genetics of an egg to produce a taller offspring. Terms like “designer babies” have been thrown out to represent the prospect of adjusting germline cell genetics to achieve valued physical attributes.
Conducting gene therapy with equal access, proper consent, and appropriate goals should be a universal objective. These treatments are not harmless, so proper utilization is essential. For instance, gene editing methods could cause DNA changes at unintended sites. Another potential adverse effect is an immune system reaction, triggered by the creation of new proteins based on a new genetic code. The new proteins could be identified as foreign by the patient’s immune system, leading to allergic-like, severe immune responses. Even the viral vectors used to deliver genetic material can be harmful at times. While progress in gene therapy is picking up, the adverse effects, social questions, and ethical considerations continue to be limiting factors for good reason.
Summary
In recent years, gene therapies have reached major milestones. FDA approval has been achieved for use in the treatment of multiple types of cancer and genetic disease. Researchers are pushing forward on numerous fronts to make gene therapy a reality for other disease states. As excited and impatient as we are prone to be, the next steps in utilizing gene therapies must be taken with a cautious assessment of ethical and safe use.
