What is gene therapy?

By Pekka Simula 27 October 2016

Lymfactin® is a gene therapy currently in clinical development for the treatment of certain types of lymphedema. So what exactly is gene therapy, other than a phrase that triggers jokes of growing a third eye in the middle of our forehead?

Gene therapy is actually a wide umbrella term covering any therapies involving some genetic modification. The hard-core form of gene therapy means an attempt to replace defective genes in patients with genetic disorders. For instance haemophilia is caused by a defective (typically inherited) gene, due to which the patient’s blood doesn’t clot well.

Such diseases cannot be treated easily with conventional medicine because the defect is in every cell. Even if traditional drugs can help the symptoms they won’t cure the disorder. Gene therapy could really cure the disease: If the correct gene was introduced to a large enough number of defective cells, the correct gene would carry on when those cells divide and the patient might actually be cured. Typically, gene therapies like this aim to target somatic cells only, as modifying genes in germ line cells is ethically complex.

A softer form of gene therapy means using a genetically modified microorganism (for instance a virus) as a drug, without modifying the patient’s own genes. Good examples are viruses whose genome is modified to infect cancer cells instead of normal healthy cells. Such oncolytic viruses can be used like any anti-tumor medicine; the drug just contains viruses instead of a drug molecule. The intention is still the same: Give the patient something that is more harmful to cancer cells than to normal cells.

Even simpler, gene therapy can mean a genetically modified microorganism, which is coded to help the patient produce a drug. Lymfactin® belongs to this category. Patients with lymphedema have defects in their lymphatic system. In breast-cancer associated lymphedema the usual cause is surgery or radiotherapy, which has damaged lymph nodes in the armpit. The obvious cure would be growing new lymphatic vessels in the damaged area. A protein called VEGF-C has been identified that promotes just that. However, if the VEGF-C protein was injected in the armpit it would be cleared by the human body much too fast to provide any measurable benefit. Based on preclinical testing this challenge has been overcome by gene therapy. Instead of containing VEGF-C, Lymfactin® contains viruses coding the human gene for VEGF-C, which is activated after administration. So the idea is to have the patient’s cells manufacture the patient’s own drug! Lymfactin® is expected to keep producing VEGF-C for long enough to actually make a difference. This has proven successful in preclinical disease models of lymphedema.

Regardless of this rough classification, gene therapy is most commonly implemented using nature’s own gene technology experts: Viruses.

Viruses cannot replicate on their own. Instead they are specialized in entering host cells of another organism and plug their own DNA (or RNA) in the host cell’s DNA duplication machine. The host cell then creates copies of the virus. This parasitic approach can be harnessed by modifying the virus genetically so that the DNA inserted in the patient’s cells will do something good instead.

Obviously this isn’t easy. Scientific advances seldom happen overnight. Gene therapy was proposed more than four decades ago and the first clinical studies started more than thirty years ago. After plenty of hope, hype, and failure, gene therapy finally seems to be approaching prime time. In Europe, the first gene therapy product Glybera® was approved in 2012 and many phase 3 studies are ongoing. Ethical rules and safety regulations have developed hand in hand with the science, and for instance in Finland the regulatory authorities are already experienced in clinical trials with several gene therapies.

Simple is often good when introducing novel technologies. Our Lymfactin® is a relatively simple gene therapy: Instead of modifying the patient’s genome it contains a human gene that produces a therapeutic protein, which is already naturally present in our bodies, and will be used for its natural purpose. The carrier of this human gene is a common virus rendered harmless. The virus itself is cleared quite rapidly by the human immune system so there is no need to “switch off” the treatment. Lymfactin® is still a biological drug and much more challenging to manufacture than traditional drugs; however it is developed for the treatment of breast-cancer associated lymphedema, a disease where traditional drugs offer no relief. We believe this is one of the many areas where gene therapy can make a huge difference to chronically ill patients.

Herantis has started patient treatments with Lymfactin® in a clinical study in breast cancer associated lymphedema. This is the first time in the world when gene therapy is used clinically to repair damages of the lymphatic system. Lymfactin® is based on research at a national centre of excellence at the University of Helsinki, lead by academy professor Kari Alitalo.