The Rise of Cell and Gene Therapies in Treating Complex Diseases

Cell and gene therapies represent transformative approaches to medicine, wherein cells or genetic material are used to treat, prevent or potentially cure disease. Historically, cell therapies have mostly consisted of procedures using unmodified cells, such as bone marrow transplants. However, over the past decade, advancements in synthetic biology have enabled extensive engineering of cells, allowing us to imbue immune cells with new abilities.

CAR T-cell therapies, for instance, are created by modifying the genome of immune cells. These genetically engineered cells – which can be produced from autologous (from the patient) or allogeneic (from a donor) sources – are infused into the patient where they have new disease-targeting capabilities. Similarly, gene therapies introduce genetic material, be it DNA or RNA, into affected cells of the body to correct a disease-causing process. Some treatments combine both approaches, such as engineering stem cells to express or silence genes and reintroducing them into the patient.

Together, cell and gene therapies are paving the way for personalized medicine across a wide range of diseases.

Diseases and conditions targeted by gene-editing therapies

Gene-editing therapies are being developed for a wide array of conditions, from hematological and solid tumor cancers, genetic disorders like spinal muscular atrophy and cystic fibrosis and even autoimmune diseases such as lupus and multiple sclerosis.

The list is varied, but each application shares a common theme – they all leverage gene-editing technology to target conditions where the modification of a specific genetic element can help halt or reverse disease progression. This may involve direct editing of a disease-causing mutation or modification of other genes that can influence disease presentation. 

For example, sickle cell disease is caused by mutations in the hemoglobin gene that result in sickling of the hemoglobin protein. One recently approved gene therapy, CASGEVY^TM (exagamglogene autotemcel), uses CRISPR-Cas9 technology to trick the body into producing fetal hemoglobin. In doing so, the fetal hemoglobin can compensate for and dilute the disease-causing sickled hemoglobin.

It’s worth noting that not all gene therapies involve editing DNA. In conditions like Duchenne muscular dystrophy, exon-skipping techniques alter RNA splicing without modifying the underlying DNA to partially correct the disease phenotype.

CRISPR: A breakthrough technology in gene editing

CRISPR is a gene-editing tool that was originally discovered in bacteria where it functions as an adaptive immune system that defends against viruses. Several important modifications over the past decade have allowed scientists to wield CRISPR components, CAS proteins and single guide RNAs (sgRNA), to precisely target and edit specific DNA sequences.

Today, several iterations of CRISPR give researchers a variety of approaches to gene editing. Some forms of CRISPR work by eliciting a double-strand break to prevent gene expression, while others simply block or enhance a gene’s ability to recruit transcription factors or modify the gene’s epigenome.

CRISPR is considered a breakthrough technology because it is simple and effective. Other forms of gene editing, such as TALEN (transcription activator-like effector nuclease), require bespoke proteins and considerable optimization. CRISPR can be readily modified to target the specific gene of interest and there are enough tools out there now that you don’t need deep technical expertise to be effective with it.

CRISPR is available, versatile, effective and relatively cheap compared to other genome-editing technologies, all of which enable the development and scalable production of gene editing therapeutics.

Traditional CRISPR approaches rely on a certain degree of randomization. While we can specifically target CRISPR editing to a specific DNA sequence, the exact edit that’s made is not easy to control. CRISPR editing induces a double-strand break, which often results in partial deletion of the sequence and prevention of gene expression – but not always. Further, disruption to gene expression may not be wanted, but rather a correction of a mutation while maintaining gene expression.

Base editors and prime editing overcome these limitations. Base editors can directly convert one nucleotide into another without deleting neighboring nucleotides, thus preserving gene expression. Prime editing takes this further by allowing precise edits within stretches of the DNA sequence, expanding the range of potential therapeutic applications. These technologies enable more reliable and efficient gene correction, making them valuable for conditions caused by specific genetic mutations. Another key advantage of base and prime editors is that, unlike CRISPR-based editors, they do not produce double-stranded DNA breaks that could result in unwanted chromosomal translocations.

Using non-viral electroporation technologies to deliver gene editing tools

A key part of engineering cell and gene therapies is having the ability to deliver molecular tools to cells. These tools may be gene-editing components, such as a DNA encoding a CAS enzyme and its associated sgRNA, or it may involve the delivery of a synthetic gene encoding a new CAR construct. Whatever is being delivered, scientists need the ability to reliably and efficiently transfer molecular elements into a cell.

Traditionally this was done using viruses, such as adenovirus or lentivirus. While these can be effective tools, they are inherently limited by space – only so much genetic material can fit inside the capsid of a virus. Electroporation doesn’t have these same limitations, allowing you to reliably deliver almost anything to the cells, from large gene fragments to multiple plasmids.

This is important because gene-editing tools are becoming increasingly more complex. Modern cell therapies frequently require cells to be imbued with synthetic CAR proteins and edited material to remove potentially immunogenic proteins. Reliably delivering all of this to cells is a difficult and resource-intensive process when using viruses. However, with electroporation, the process is simplified and becomes far more dependable. Additionally, the biological risks associated with electroporation are far less relative to viruses (requiring fewer biosafety precautions) and can be automated, making it ideal for large-scale operations. Finally, electroporation allows the co-delivery of different loading agents, including RNPs, mRNA and DNA.

Electroporation ultimately enables complex cell engineering strategies that are not possible with viral delivery methods that are generally restricted to a single category of molecular payload.

A question of ethics

There are several interesting ethical concerns that we as scientists and a society need to grapple with.

At a high level, gene editing gives us the ability to modify a person’s traits by altering their DNA. However, some risks go with this. We do not yet have a perfect understanding of human genomics and the full ramifications of certain edits may be unknown. Currently, gene editing is only being used to address serious medical conditions, where the risk-reward ratio makes it easy to accept these unknown risks.

But the day may soon come when we begin to apply gene-editing technology to correct less severe conditions. At what point do the risks of gene editing outweigh the benefits to the patient? Further, we will need to consider the possibility and ramifications of germline editing where modifications can be passed on to future generations.

None of this is particularly new. Society is continually grappling with the ethics of personal choice in medicine, challenges of equity and how we treat disability. Ultimately, our technologies – both old and new – are a product of our culture and are thus likely to be influenced by our existing biases. At the same time, these technologies have great capacity to help save lives. Therefore, we must continue working together to find an ethical path forward to maximize societal benefit and minimize harm.  

Significant milestones achieved in 2024

The field of cell and gene therapy witnessed transformative advancements in 2024, marking key milestones in patient care.

Vertex’s CASGEVY gained US Food and Drug Administration (FDA) approval in January 2024, becoming a groundbreaking CRISPR-based therapy for beta thalassemia and achieving its first commercial treatment for sickle cell disease. Similarly, bluebird bio’s LYFGENIA™ (lovotibeglogene autotemcel), one of the first two FDA-approved gene therapies for sickle cell disease in 2023, reached its first commercial use in June 2024. In oncology, Lifileucel became the first tumor-infiltrating lymphocyte therapy approved for advanced melanoma. The field also expanded into new therapeutic areas, including the first use of allogeneic cell therapy for autoimmune disease, and saw notable growth in clinical trials targeting non-cancer-related conditions. These developments underscore the rapidly evolving landscape of cell and gene therapies.

The outlook for 2025

The future of cell and gene therapies is incredibly bright. Building on key 2024 milestones, 2025 will likely bring further advancements in allogeneic cell therapies, CRISPR-based treatments and the development of therapies targeting solid tumors, autoimmune diseases and rare genetic conditions.

Large-scale manufacturing of off-the-shelf allogenic cell therapies is of great interest and 2025 is likely to see gains in this area. Advancements in gene editing technology are making it possible to engineer cell therapies to a higher degree, reducing their potential for side effects (like graft vs host disease) and making cell and gene therapy far more accessible to patients.

The future is just as bright for autologous therapies as the industry continues to come together to streamline and automate the development and manufacturing processes, which will help increase patient access to life-saving therapies.

Cell and gene therapy applications beyond cancer will continue to grow, likely with notable examples in autoimmune disease. 

Technologies like electroporation will continue to accelerate these developments, unblocking barriers that are common with viral technologies and enabling the delivery of complex genetic tools at scale.

The coming year will not only expand the reach of these therapies but also solidify their role as transformative solutions for some of medicine’s most challenging diseases, from solid tumors to rare and previously untreatable diseases.