Gene therapies can be a one-time treatment with the aim to address the underlying cause of a disease. By inserting new genetic material, disease-related malfunctions can be restored, but on the flip side, these long-lasting effects increases the risk of delayed adverse effects.

Conventional therapeutics are relatively easy to design and optimise and many of them are easily taken orally. What makes advanced therapies so extraordinary is that they reprogram basic biologic functions in the human body to target the cause of a certain disease. Although both approaches are valuable, medical innovation is progressing from a one size fits all towards more personalised medications to treat specific groups of patients with unmet need.

Proteins have different functions; they create structures, they can facilitate biochemical reactions in the body, and they can carry signals with different instructions for the body to respond to. Protein synthesis is the process in which cells make proteins, copying the genetic code from the DNA (transcription) in the cell nucleus via a messenger RNA (mRNA) which is transported out of the nucleus and becomes translated into a protein in the outer part of the cell.

Most of the DNA do not code for proteins and is pragmatically called non-coding, initially referred to as junk DNA. Even if scientists haven’t pinned down every corner of the genome, we now know that some of the ‘junk’ give rise to RNA molecules that can regulate gene expression. Whereas mRNA is transcribed from genes coding for specific proteins, other RNA molecules such as short interfering RNA (siRNA) and micro-RNA (miRNA) are non-coding RNAs.

mRNA - carrying the message

mRNA serves as the carrier of the genetic information from DNA to protein.  New proteins can be introduced in the body and restore functions linked to disease.  Besides the most known mRNA therapies, the vaccines against covid-19, (which are, in fact, not classified as a gene therapy) additional applications have expanded to cancer immunotherapy, genetic engineering, protein replacement therapy, and mRNA-based gene editing.

Manmade, synthetic mRNA provides a template for the synthesis of any given protein, which makes it a versatile option for targeting disease mechanisms. In cancer immunotherapy, the mRNA can be custom-made to target cancer-specific markers, training the immune system to recognise and destroy these tumour cells.

Using synthetic mRNA can be a challenge since they have a short lifespan; they are easily degraded through an elimination process targeting molecules that is either no longer required in the cell or has aberrant features.  Upon entering cells, RNA molecules can cause damage by provoking a strong activation of the immune response.

siRNA – silencing the message

In 2006 the Nobel Prize for Medicine was rewarded for ground-breaking work that revealed a novel RNA-based mechanism for gene-silencing, called RNA interference (RNAi). siRNA has gained attention as a potential therapeutic reagent due to its ability to interfere with specific genes in many genetic diseases and silence their expression.

When a gene is being transcribed into an mRNA, the synthetic siRNA interacts and degrades the mRNA before it is translated into a protein. RNA interference is, at least in theory, a very specific way to knock down the expression of disease related genes as the siRNA sequence completely matches the sequence of the mRNA, when it binds and initiates the degradation. However, the therapeutic use of siRNAs is limited by challenges such as the stability and the delivery of the siRNA to its intended site of action.

siRNA holds promising prospects in drug development, especially against undruggable targets for the treatment of cancer and other diseases. This means that the developers do not depend upon finding a specific marker to bind to on a protein for the therapy, something that in oncology can be very difficult – siRNA interferes upstream of traditional therapies, targeting the genetic code before it is made into a protein.

miRNA – degradation, activation, or regulation

miRNAs are a class of naturally occurring, small non-coding RNA molecules involved in virtually all physiologic processes such as cell growth and differentiation, metabolism, and inflammation. They are associated with a wide variety of human diseases where dysregulation of the miRNAs emerges as attractive targets for disease diagnostics and intervention.

miRNA can, like siRNA bind to and initiate suppression or degradation of mRNA before it translates into a protein. Whereas siRNA typically triggers a more specific gene silencing, miRNA may interfere with the expression of several different target genes simultaneously. Abnormal expression of miRNA, either too high or too low to regulate the cells properly, has been implicated in many human cancers, heart disease or neurological disorders.

The challenges are similar to siRNAs, with the addition that, since a single miRNA might target numerous mRNAs implies the possibility of unpredictable side effects, even if the intended miRNA is effectively targeted. There have been major advances in the field of miRNA, but some hurdles remain in the areas of targeted delivery, stability, specificity, toxicity, and immune system activation.

ASO antisense oligonucleotides

Antisense technology is a precise, rapid, and potentially high-throughput approach for inhibiting gene expression through recognition of cellular RNAs.

As described in the beginning, mRNA transcribes a part of the gene from the DNA. The DNA is made of two strands of building blocks, paired together and when translated, the strands open up and the mRNA is built to form a single strand of the code that will result in a protein. This mRNA strand is called the ‘sense’ strand. The antisense sequence is complementary and can interlock with the mRNA, ‘occupy’ it and therefore inhibit the translation. This occurs in the same precise manner as in mRNA transcription or when cells divide, and the DNA is duplicated.  

One type of ASO therapy is exon skipping which is a therapy for Duchenne Muscle Dystrophy (DMD). DMD is caused by a mutation in the dystrophin gene (the largest known gene in humans) and parts of the genes (exons) are missing. In exon skipping, the ASO allows the other parts of the gene to join together to construct a protein that is shorter than usual but may have some proper function.

Gene editing – cutting into the genome

Gene editing can be used to correct, introduce, or delete almost any DNA sequence in many different types of cells and organisms. Techniques to modify DNA have existed for several decades but new methods have made genome editing faster, cheaper, and more efficient. In 2020, the Nobel Prize in Chemistry was awarded to the CRISPR/Cas9 method – the ‘gene scissors’ which is the most widely used technique to edit the genome. It is an RNA-based system and works by cutting a DNA sequence at a specific location to either delete or insert DNA sequences making small or large changes in the genes, and subsequently the expression into proteins.

The beauty of the method is its simplicity. The success of CRISPR-associated gene editing depends on the selection of an appropriate RNA sequence and there are several online tools with user-friendly interfaces to support the selection of efficient RNAs with low off-target effects. The major holdup for CRISPR in clinical use is to make the delivery more efficient and specific. Researchers are exploring the options with different carriers and more direct ways to place the therapeutic components into the cells.


The possibilities of gene therapy hold much promise, but several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

  • Finding a reliable way to deliver genetic material into cells
  • Targeting the correct cells
  • Reducing the risk of side effects

As most gene therapies are designed to achieve permanent or long-lasting effects in the human body this inherently increases the risk of delayed adverse events and patients will therefore require a long period of monitoring. However, gene therapy continues to be a very important area of research to develop new, effective treatments for a variety of severe diseases.

At NDA, we have supported over 50 gene therapies, contact our team by using the form below to discuss the right strategy for your product.


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