Clinical Research: Phase 1 - Phase 4

Gene Therapy 101: From the 1960s to Today

Gene therapy is a hot topic in clinical research today — and for good reason! These technologies have the potential to treat — and in some cases even cure — a wide range of conditions, including rare genetic disorders that previously had no effective therapies.

What Is Gene Therapy?

Gene therapies are a diverse group of tools that deliver genetic material (DNA or mRNA) with the goal of providing therapeutic and possibly even curative benefits. In short, it’s using DNA to treat diseases. But just how does gene therapy accomplish this? Products currently undergoing investigation mainly rely on the following strategies:

  • Replacing a mutated copy of a gene with a healthy one. If done early enough, some of these therapies may be able to cure serious pediatric diseases
  • Inactivating or “knocking out” a mutated gene that is functioning improperly
  • Introducing a new gene into the body to help fight a particular disease. Examples are the cancer-fighting treatments of this type that have already gone to market and a number of HIV treatments currently in clinical trials.

A Brief History of Gene Therapy

Although the technologies necessary to make human gene therapy a reality are fairly recent, as a concept first introduced in the 1960s, the idea is more than half a century old. In fact, scientists were able to incorporate functional DNA inside human cells in vivo as early as 1961. However, early attempts at gene transfer were extremely inefficient, and the handful of clinical trials attempted proved unsuccessful.

A major turning point happened in 1983 when scientists at MIT created the first retroviral vector suitable for use in gene therapy from a mouse leukemia virus. Another piece of the puzzle came together in 1984 with an experiment that showed targeted insertion of corrective DNA was possible in mammalian cells in vitro. Anticipating a mounting need, the NIH then published its first guidelines for human cell gene therapy experiments not long after.

Gene therapy as a viable concept was proven by the National Cancer Institute and NIH in 1990. One widely publicized example was the treatment of a girl with adenosine deaminase deficiency, a genetic defect that causes severe combined immunodeficiency. A working version of the gene was introduced to compensate in making the enzyme that she lacked. Although treatment was considered successful, it only worked for a short time.

Although the 1990s brought further innovations, such as the first use of hematopoietic stem cells as vectors to deliver corrective genes, there were also major setbacks for gene therapies. The widely publicized death of Jesse Gelsinger in 1999, who died following a major immune response to a vector used in clinical trial, had a major negative impact on the field.

However, in 2012 regulatory authorities granted approval to Glybera, the first gene therapy for the European market, for the treatment of lipoprotein lipase deficiency. Although effective, the therapy was a commercial failure with only one patient with this rare disease undergoing treatment.

The US only recently approved its first in vivo gene therapy treatment toward the end of 2017 in the form of Luxturna. This promising therapeutic has been shown to dramatically improve the vision of young patients with a severe and relatively common form of retinal dystrophy. Previously, these patients were likely to completely lose their sight before reaching adulthood.

Gene Therapy Research Today

As of the end of 2017, more than 2,400 gene therapy trials have been conducted. Of these, the majority (64.6 percent) have been for oncology indications, mostly as Phase 1 trials. Clinical trials for monogenic diseases are the second most common at 10.5 percent. These represent conditions caused by a single known and targetable gene and frequently fall under rare diseases. Some of the most well-known examples of these include lysosomal storage diseases, Duchenne muscular dystrophy, Huntington’s disease, cystic fibrosis, and hemophilia. Infectious and cardiovascular diseases are also common indications for gene therapy trials with each making up roughly 7.4 percent of trials to date.

Gene Therapy Vectors and Delivery Systems

With such a wide variety of indications, it isn’t surprising that there is no universal vector for delivering gene therapy.

Viral Vectors

Adenoviruses make up the majority of gene therapies under investigation. However, other viral vectors have been derived from adeno-associated viruses, herpes viruses, and retroviruses, such as lentiviruses. To create a safe vector, the normally pathogenic viruses are engineered to remove the section of their genetic code that can cause disease while still retaining the genetics that allows them to infect and reproduce inside cells.

Viral vectors harness evolution to do what they do best: deliver genetic information that can be targeted to the cells that need it most. For example, vectors for the treatment of cystic fibrosis are selected to target epithelial cells and vectors for Duchenne’s target muscle cells. In this way, target cells ultimately dictate what type of delivery system can be used and, in turn, operational challenges that must be addressed.

Specific viral vectors are selected based on:

  • How well they transfer genes to the cells they recognize and are able to infect
  • Whether or not they integrate with the host DNA
  • How long the introduced genes are expected to be expressed by the host cell
  • The size and structure of the virus

Non-viral Vectors

Non-viral vectors are naked DNA or DNA complexes, such as oligonucleotides, lipoplexes, and polyplexes, that are not packaged with a virus. These vectors are able to transfer relatively large genes, such as dystrophin, compared with viral vectors. Non-viral vectors are also significantly less likely to provoke an unwanted — and potentially dangerous — immune response.

Engineered Nucleases

Nucleases can be thought of as “molecular scissors” that can insert, delete, or replace DNA in the genome of an organism. Well-known examples are zinc finger nucleases and transcription activator-like effector nuclease (TALEN). The CRISPR/Cas9 system deserves special attention as a genome-editing tool that can be targeted with unprecedented ease and precision.

Operationalizing Gene Therapy Trials

Gene therapies are a promising strategy for effectively treating a wide range of diseases. Unfortunately, their complex and revolutionary nature also makes running successful clinical trials especially difficult. Luckily, sponsors interested in bringing their gene therapies to market can reach out to experienced CROs, consultants, and specialized vendors for help.