Principles of Gene Therapy

What is Gene Therapy?

An overview of gene therapy and some of the key concepts in this field

Loren del Mar Peña

Associate Professor of Pediatrics at the University of Cincinnati, Ohio

Presented By:

Loren del Mar Peña

Associate Professor of Pediatrics at the University of Cincinnati, Ohio

Dr. Loren del Mar Peña is Associate Professor of Pediatrics at the University of Cincinnati, Ohio. She completed her PhD at Northwestern University, Evanston, Illinois in 2002, received her MD at Northwestern University, the Feinberg School of Medicine, Chicago in 2004 with residencies in pediatrics and clinical genetics at the University of Chicago. She specializes in the diagnosis, treatment, and management of hereditary diseases. She is a clinical geneticist and trialist in the orphan disease arena, with expertise in implementation of studies for rare and ultra-rare disorders. Dr. Peña has served as principal investigator in multiple clinical trials focused on rare disorders and spanning different treatment approaches that include gene therapy. She has also described several new genes involved in rare disorders.

[The transcription below is of the video at the top of this page.]

Welcome, my name is Dr. Loren Pena and I’m the Associate Professor of Pediatrics at the University of Cincinnati in Ohio. In this chapter, I’m going to give you an overview of gene therapy and explain some of the key concepts in this new and exciting field.

Gene therapy is the alteration of genes in order to treat diseases1,2. We can approach gene therapy in several different ways3,4: by compensating for a mutated gene by adding a non-mutated version, by adding a new gene to aid in treatment, by deactivating a mutated gene that is not functioning properly, by editing a gene to introduce targeted changes, or by engineering the body’s own immune cells to attack disease cells.

Gene therapy can be divided into two main types: Somatic gene therapy and germline gene therapy1.

Somatic gene therapy involves the alteration of genetic material in diploid cells, replacing mutated or missing disease-causing genes with functional normal ones, inhibiting expression of abnormal genes, or adding a new gene to aid in treatment of a disease2. One major advantage of this approach is that the effects are limited to the patient and targeted to specific cells or tissues within their body1.

Germline gene therapy involves the direct manipulation of oocytes, sperm, zygotes, or embryos, but due to ethical concerns, it is banned or restricted in countries with active research programs2,3. Throughout the rest of the learning units when we talk about gene therapy we will only be discussing somatic gene therapy.

There are two distinct methods for delivery of somatic gene therapy1.

Ex vivo, or cell-based gene therapy, involves the collection of cells from the patient, the modification of those cells in culture, then the expansion of the cells and injection back into the patient.

In vivo delivery involves direct delivery through injection into the patient. In vivo delivery has the advantage that it avoids the practical issues of cell collection, culture, manipulation, and expansion required for ex vivo-based therapies.

Gene therapy is currently under investigation in clinical trials across a wide range of conditions, including: Inherited diseases such as spinal muscular atrophy, inherited eye disease, hemophilia, cystic fibrosis, muscular dystrophy, and Huntington’s disease; and complex disorders, such as cardiovascular diseases and cancers. Cancer types under investigation include acute lymphoblastic leukemia, B-cell lymphoma, prostate, colorectal, breast, lung, and cervical cancers. Gene therapy is also under investigation for infectious diseases, such as HIV and hepatitis C.

Several gene therapy treatments have already been approved and are being marketed. Since 2016, three ex vivo-based treatments have been approved.

These treatments are:

Strimvelis – a treatment for the severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID, which was first approved for use in 2016 by the EMA.

Kymriah – a treatment for acute lymphoblastic leukemia and B-cell lymphoma, which was first approved by the U.S. FDA in 2017.

And Yescarta – a treatment for B-cell lymphoma first approved in 2017 again by the U.S. FDA.

To date, two in vivo treatments have been approved and are being marketed.

These treatments are:

Gendicine – a head and neck squamous cell carcinoma treatment, which the State Food and Drug Administration of China approved in 2003, and Luxturna – a treatment for biallelic RPE65 mutation-associated retinal dystrophy, which was first approved by the U.S. FDA in 2017.

So, in summary:

Gene therapy involves therapeutic manipulation of genetic material to treat a disease and is focused on somatic therapies, involving either in vivo or ex vivo delivery methods1,2.

Gene therapy has already been approved for selected indications, and clinical trials of gene therapies are ongoing in several fields of medicine3.

In our next chapter, the interactive timeline of “The History of Gene Therapy”, we’ll look at the fascinating story since the 1970s, when the idea that good DNA could be used to replace defective DNA was first suggested, and how the exciting scientific and clinical advances since then have made gene therapy a reality.