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  6. What is Cell and Gene Therapy?

What is Cell and Gene Therapy?

  

Cell and gene therapy are closely related fields that use biological materials or substances to treat diseases. Cell therapy involves using cells (typically stem cells) to replace or repair damaged or diseased tissue, as they can differentiate into various cell types. In other words, they can regenerate damaged tissue in conditions such as Parkinson’s disease, heart disease and diabetes.

Another type of cell therapy is gene-modified cell therapy, in which immune cells (T-cells or NK cells) are genetically modified to target cancer cells overexpressing certain cancer markers. If harnessed properly, they could become a powerful tool in fighting against cancer due to the cytotoxicity of these immune cells.

Gene therapy involves using genes to treat or prevent diseases. It can include replacing or repairing defective genes, adding new genes to help the body fight disease or using genes to modify cell behavior. It can also modulate gene expression through the introduction of gene fragments. Gene therapy can address genetic disorders, including cystic fibrosis, sickle cell anemia and certain types of cancer and viral infections.

Cell and gene therapy have shown tremendous promise in treating many diseases and have been approved for clinical use in some cases. However, these therapies are still relatively new, and thorough research is required to fully understand their potential and risks.

What are cells and genes?

Cells are the basic building blocks of all living organisms and are the smallest unit of life that can exist as individual cells or part of a larger organism. Cells can vary in size, shape, and function depending on their specific role in the body.

Some important examples of cells include red blood cells that carry oxygen throughout the body and nerve cells that transmit signals between the brain and the rest of the body.

Genes are the units passed down from parents to their offspring. That’s why they are also called heredity units. They are segments of DNA (deoxyribonucleic acid) that contain the instructions for building and maintaining an organism.

Additionally, genes help determine many of an individual’s physical and biological characteristics, including eye color, hair color, and height. They can also influence a person’s susceptibility to certain diseases.

Subtypes of cell therapy

Cell therapy is a medical treatment type that uses cells to repair, replace or regenerate damaged or diseased tissue. It is a regenerative medicine with great promise for treating various conditions, including cancer, autoimmune diseases and genetic disorders.

A common way to group cell therapy is through the cell type used. There are several types of cell therapy, including stem cell therapy, immune cell therapy and tissue engineering. Stem cell therapy uses stem cells that can differentiate into various cell types to regenerate damaged tissues.

Immune cell therapy involves using immune cells such as T-cells and natural killer cells to fight cancer or other diseases, often called gene-modified cell therapy. Tissue engineering involves using cells, scaffolds, and growth factors to create new tissue in the laboratory, which can then be transplanted into the body.

Cell therapy may revolutionize the way we treat many diseases and injuries. However, many challenges exist, including developing safe and effective methods for delivering cells to the body, ensuring that the cells are compatible with the patient’s immune system and addressing ethical concerns surrounding the use of embryonic stem cells.

Subtypes of gene therapy

The common way to group gene therapy is through their mechanism of action. There are several types, including viral vector, non-viral gene editing and gene silencing.

  • The viral vector approach uses an engineered viral capsid, usually lentiviral, adeno, and adeno-associated viral vector, to deliver the gene of interest to target cells.
  • The non-viral approach involves using gene-editing molecules, such as CRISPR-CAS9 and MEGA-TAL, to deliver or alter the gene of the target cells.
  • The gene-silencing approach involves using shRNA or siRNA complementary to the targeted mRNA in the gene expression pathway, thus interfering with and silencing the gene expression in the target cells.

When characterized by the target cell types, we can classify gene therapy into somatic or germline gene therapy. Somatic gene therapy involves the transfer of genetic material into the patient’s somatic cells. However, the genetic changes made in these cells are not passed to future generations.

In contrast, germline gene therapy involves the transfer of genetic material into the cells that produce eggs or sperm. The genetic changes made in these cells can be passed to future generations. However, due to ethical and safety concerns, germline gene therapy is experimental and controversial.

How do cell and gene therapies work?

Cell and gene therapy involves using genetically modified cells as a therapeutic approach to treat diseases. The therapy typically involves modifying cells to express a desired therapeutic protein or acting as a delivery vehicle for therapeutic genes.

Cell therapy requires that cells from the parent or a donor be genetically modified to perform a specific therapeutic function. For example, immune cells are modified to recognize and destroy cancer cells. In another example, stem cells can help regenerate damaged tissues in patients with degenerative diseases.

Gene therapy requires introducing a specific gene into a patient’s cells to treat a disease. This gene is delivered directly to the target cells or incorporated into a vector, such as a virus, to deliver the gene to the cells.

How do cell and gene therapies target diseases?

Designing cell and gene therapies typically includes targeting strategies. The strategies could be immunoadoptive for gene-modified cell therapy and tissue-specific delivery for gene therapy. These strategies are viewed as the paths to precision medicine and are discussed in detail below:

Gene-modified Cell Therapy

A type of therapy gaining momentum is CAR-T therapy or Chimeric Antigen Receptor T-cells. The strategy is to introduce a CAR to the surface of the patient’s T-cells. A typical design of CAR consists of CD3 transmembrane domain, an intracellular costimulatory domain and an extracellular binding single-chain variable fragment (ScVf). Through the immunological affinity of the ScVf, the CAR-T cells can target the cancer cells overexpressing a specific biomarker, for example, CD19.

Viral Vector Gene Therapy

As mentioned, this gene therapy uses viral capsid to package and deliver a gene of interest to the target cells. Depending on the serotypes of the viral vector, tissues are targeted to certain tissue types in our body.

For example, the AAV2 serotype is known to have high specificity for the kidney, whereas the AAV8 serotype has high specificity for the pancreas. To illustrate this, an FDA-approved AAV therapy utilizes AAV9 to deliver a missing gene from the hereditary disease to the patient’s neuron cells in the central nervous system.

Lipid Nanoparticles and SORT

A recently discovered technique and strategy is to add a supplemental component, such as DOTAP lipid, to the formulation of lipid nanoparticles. This design, called selective organ targeting (SORT), creates a highly tissue-specific delivery system based on the percentage of the supplemental component. This strategy shows promising applications with RNA -type therapies and CRISPR-based therapies.

The difference between cell therapy and gene therapy

Cell therapy and gene therapy are two different approaches to treating diseases at the molecular level. Cell therapy involves using live cells, typically from the patient or a donor. Gene therapy, however, involves modifying the patient's genetic material, such as inserting, deleting, or altering genes, to treat a disease.

Is cell or gene therapy more effective?

Cell and gene therapy's effectiveness depends on the disease or condition being treated and other factors such as the patient's medical history, current health conditions, treatment plan and goals, lab results and more.

For example, cell therapy may be more effective in treating conditions that involve replacing or regenerating damaged tissues, such as spinal cord injuries or heart disease. On the other hand, gene therapy may be more effective in treating genetic disorders, such as cystic fibrosis or sickle cell anemia, in which a specific gene mutation is the underlying cause of the disease.

Patients and their healthcare providers should consider several factors when deciding on the most appropriate treatment. First, patients and providers should review several factors, including medical history, current health conditions and treatment goals to help determine if either therapy is appropriate for their situation.

Additionally, patients should also consider the risks and benefits of each therapy. Cell therapy may carry risks such as infection, rejection or other complications. Gene therapy may carry complications such as immune reactions or unintended effects on other genes. Patients should discuss these risks with their healthcare provider and carefully weigh them against the potential benefits of the therapy.

Moreover, patients should also consider the availability and cost of each therapy. Cell therapy may be more readily available and less expensive than gene therapy in some cases, while gene therapy may be more specialized and costly.

FDA approved cell and gene therapies

The US Food and Drug Administration (FDA) has approved several cell and gene therapies for clinical use. Here are a few examples:

Kymriah and Yescarta

These therapies are CAR-T cell therapies that use genetically modified T-cells programmed to target and destroy cancer cells. Kymriah and Yescarta, have been approved by the FDA to treat certain blood cancers.

Luxturna

This gene therapy treats inherited retinal diseases caused by mutations in a specific gene. Luxturna delivers a functional copy of the mutated gene to the patient's retinal cells to help restore restoring vision.

Zolgensma

This gene therapy treats spinal muscular atrophy (SMA), a rare genetic disorder that causes muscle weakness and loss of motor function. Zolgensma delivers a functional copy of the SMN1 gene to the patient's cells, which helps to improve muscle function and increase lifespan.

Provenge

Provenge is a cell therapy that treats advanced prostate cancer. It involves collecting a patient's immune cells, genetically modifying them to target cancer cells and then infusing the cells back into the patient's body.

Alofisel

This cell therapy helps treat complex perianal fistulas in patients with Crohn's disease. It involves collecting a patient's stem cells, which are then expanded in the laboratory and infused back into the patient to promote tissue repair.

Cell and gene therapy research

Research in cell and gene therapy is crucial for developing new treatments and improving existing therapies. Some of the biggest research projects around cell and gene therapy treatments include:

  • The Human Genome Project: This project aimed to sequence the entire human genome and has provided a wealth of information about genetic mutations and diseases.
  • The Cancer Genome Atlas: This project involves the genomic analysis of thousands of cancer samples to identify genetic mutations that are targetable with cell and gene therapies.
  • The International Human Epigenome Consortium: This project aims to map the epigenome, which refers to changes in gene expression that are not caused by alterations in the DNA sequence. This information can help develop new epigenetic therapies.
  • The National Institutes of Health Somatic Cell Genome Editing Program aims to develop new technologies for the therapeutic editing of genes in somatic cells.
  • The Stem Cell Network: This Canadian research network brings together scientists, clinicians, and industry partners to develop stem cell therapies for various diseases.
  • Cell and gene therapy research is rapidly advancing and holds great promise for developing new and more effective treatments for various diseases.

Cell and gene therapy manufacturing challenges

Cell and gene therapies are rapidly emerging as promising treatment options for various diseases, including cancer, genetic disorders, and autoimmune diseases. However, manufacturing these therapies on a large scale poses several challenges, discussed in detail below.

Manufacturing Complexity

Cell and gene therapies are complex products that require specialized manufacturing processes. Manufacturing cells and genetic material involve complex biological processes that can be challenging to scale up for mass production.

Quality Control

The quality of cell and gene therapies is critical, and rigorous quality control measures are essential to ensure the safety and efficacy of these products. However, ensuring consistency and quality control for cell and gene therapies is more challenging than traditional pharmaceutical products.

Regulatory Challenges

Strict regulatory guidelines from agencies such as the FDA and European Medicines Agency (EMA) regulate cell and gene therapies with specific manufacturing, clinical testing and commercialization guidelines. Meeting these regulations can be time-consuming and expensive.

Cost

Manufacturing cell and gene therapies can be expensive, which can make these treatments unaffordable for many patients. Reducing manufacturing costs is critical to making these treatments more accessible.

Supply Chain Management

Cell and gene therapies are often customized to individual patients, which makes supply chain management more complex. Ensuring timely delivery of these products to patients can be challenging, particularly when dealing with perishable materials like cells.

Future of cell and gene therapy

Despite the challenges associated with manufacturing, the future of cell and gene therapy looks promising, with ongoing innovations and breakthroughs. Here are some areas researchers are investigating:

Off-Target Effect in Gene-Modified Cell Therapy

One of the challenges in the CAR-T design is the off-target effect. In other words, CAR-T therapy may affect cells not expressing biomarkers. A few research directions require novel CAR-T designs, for example, dual-target CAR-T therapy. Some researchers also explore the higher specificity of the T Cell Receptor (TCR) design for CAR-TCR therapy.

On-target Off-Tumor Effect in Gene-Modified Cell Therapy

While targeting a certain biomarker, CAR-T therapy can cause side effects on non-target cells expressing the same biomarker. An example is B cell aplasia, where normal B cells are depleted after cell therapy treatment. Many researchers are exploring novel biomarkers through in silico simulation or artificial intelligence. The goal is to identify biomarkers with a high specificity and a high therapeutic effect.

Immungenicity of Cell and Gene therapy

The body’s immune system could adversely affect these novel therapies. For example, an emerging technology for producing CAR-T cells is the allogeneic approach, where “off-the-shelf” cell therapy drugs are manufactured from a donor-derived cell source. However, a major hurdle is to overcome the graft-versus-host reaction. Regarding viral vectors, adenovirus and lentivirus are more prone to induce immunogenicity. As a result, adeno-associated viruses are more popular, and more research on other viral vector types could lead to a meaningful breakthrough.

Single-Gene Mutation Hereditary Diseases

Many developed gene therapy drugs target a single-gene mutation. One example is the HBB beta-globin mutation in sickle cell disease. The fundamental challenge of understanding the interplay of multiple genes could form a ceiling for gene therapy. Further research is necessary to address more complicated diseases involving multiple genes of interest.

Learn more about cell and gene therapy

Cell and gene therapies can provide significant benefits to patients who suffer from genetic or acquired diseases. Learn how Avantor is at the forefront of helping biopharma companies develop cell and gene therapies that can reach patients faster. Check out these resources on cell and gene therapies: