Gene therapy has been associated with several problems over the last few decades. One of the main issues is the lack of knowledge about the long-term effects of the therapy and the field is fraught with ethical issues.

The Weismann barrier is an important principle put forward by August Weismann that states hereditary information should only ever move from genes to cells of the body and never vice versa so as to ensure it is not fed back to germline or gamete cells (sperm and ova).

In other words, if a person has undergone gene therapy whereby the DNA content of their body cells has been modified, there should be no way that the inserted gene can be transferred to the gametes. If this rule is not followed, the therapy could lead to heritable alterations in the genome that could be passed on to future generations, rather than the effects being confined to one person.

Other challenges faced in the field of gene therapy include:

Most gene therapies are short-lived meaning patients need to undergo multiple treatments. Therapeutic DNA needs to be functional in the long-term and the cells containing it need to be long-lived and stable if the therapy is going to provide a permanent cure. However, difficulty integrating the DNA into the genome combined with the fact that many cells divide so rapidly means long-term benefits are problematic to achieve and repeated treatments are needed.
 

Disorders arising from one gene mutation are the most promising candidates for gene therapy but a lot of the most common disorders such as diabetes, heart disease and arthritis are caused by a combination of altered genes making them particularly difficult to treat.

The body's immune system can respond to the modified vectors and disrupt the effectiveness of gene therapy. The immune system's recognition of foreign bodies also means repeated therapy can become problematic.

Use of the viral vectors can also pose a risk to patients in a variety of ways by triggering toxic, immune or inflammatory reactions or through the virus itself recovering its ability to cause disease once inside the body.

There is a risk of inducing tumor growth, a concept referred to as insertional mutagenesis; if the inserted DNA is incorrectly placed, such as in a tumor suppressor gene, then a tumour may form.

Three deaths have occurred during gene therapy trials. One of the most notable was the death of 18-year old Jesse Gelsinger during a trial conducted at the University of Pennsylvania in 1999. Gelsinger was treated for a deficiency in the enzyme ornithine transcarboamylase, a condition where the liver is unable to metabolize ammonia. He died four days after the therapy due to a severe immune reaction to the viral vector used to transport his corrected genes.