Gene Therapy: Bringing Hope to the Rare Disease Community

Gene Therapy: Bringing Hope to the Rare Disease Community

Gene therapy – the idea of using genes to treat disease – is a relatively new idea and several clinical applications are still in development. This type of therapy aims to treat disease in three different ways. The most common approach is to restore the normal function of a gene by replacing a mutated gene that causes disease with a healthy copy of this gene. Gene therapy can also interrupt a mutated gene that is working improperly and contributing to disease. In other cases, an entirely new gene can be introduced to fight a disease.1 The first successful gene therapy trial was conducted in 1990 on a four-year-old girl by the name of Ashi DeSilva to treat her adenosine deaminase deficiency.2

The most difficult part of developing a gene therapy is finding a way to safely and effectively deliver genes to target cells. This usually requires the use of a vector. In early gene therapy research, viruses were seen as ideal candidates for this task. Viruses, such as HIV, make for good vectors because they replicate by integrating their genes into their host’s genome. When engineering viruses for gene therapy, the viral genes are stripped away and the gene of interest is inserted. This way, the virus will not reproduce in cells, but is still able to deliver the gene of interest into the cells of the host. The main limitation with viral vectors in gene therapy is that they integrate randomly into the genome, making it almost impossible to control where a gene would be inserted. This random insertion could prove harmful if it were to disrupt an essential gene or activate a cancer-causing gene. On the other hand, the virus could be ineffective as a gene therapy if it puts itself into a part of the chromosome that is turned off, also known as being actively silenced.

“Today, scientists have access to a more powerful gene editing tool – the CRISPR/Cas9 system.”

Today, scientists have access to a more powerful gene editing tool – the CRISPR/Cas9 system. A team of NIH researchers has conducted work in mice that shows promise in correcting an X-linked mutation that causes chronic granulomatous disease (CGD), a rare inherited immunodeficiency.3 Patients with CGD are at risk for developing life-threatening bacterial and fungal infections because they carry a mutation which affects their white blood cells’ ability to attack and kill these foreign invaders. First, researchers corrected the mutation using CGD in human blood-forming adult stem cells using CRISPR/Cas9. The CRISPR/Cas9 system can be thought of like a molecular “search and rescue mission.” It employs an enzyme that searches out the target mutation and snips it, rescuing the mutation with a DNA fragment that contains the correct sequence. Next, the human stem cells were transplanted into the bone marrow of mice where they successfully populated and matured into fully functional white blood cells. Remarkably, five months after the transplant, 10-20% of these functional white blood cells persisted in the mice. In order to bring this treatment to the clinic, researchers believe that the process will need to be scaled up. About half a million stem cells were transplanted into the mouse, whereas humans would likely need millions of edited cells in order to see the same results.

Gene therapy is targeted to the treatment of diseases with no other cures or viable treatments, and Niemann-Pick disease is one of these diseases. It is a rare and life-threatening lysosomal storage disease in which cholesterol and other lipids are not properly metabolized within the cell.4 In a study led by researchers at NIH’s National Human Genome Research Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, inserting a functional copy of the NPC1 gene was shown to decrease the severity of the symptoms associated with this rare disease in mice.5 Gene therapy for Niemann-Pick disease also has the potential to treat other rare diseases with similar clinical features, such as mucolipidosis IV, Batten disease, and Danon disease.

Glybera was the first gene therapy approved in the Western world. It is used in the treatment of adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD), a rare disease which affects about one per million people worldwide.6 Before using this treatment, individuals must undergo a genetic test to confirm their disease. Glybera is only used in extenuating circumstances in which patients with LPLD are following a strict diet limiting their fat intake, yet still experience severe or multiple pancreatitis attacks. UniQure, the company behind Glybera, is also working on developing gene therapies for Huntington’s disease and congestive heart failure.7 In December 2016, the company released information from its Phase I/II clinical trial using their AAV5 viral vector in patients with severe hemophilia B.

Gene therapy provides hope for a cure to several rare diseases. Unlike other treatments, gene therapy aims to treat the root cause of the disease instead of the symptoms. It can provide a permanent solution for individuals who may otherwise be on medications for the majority of their life, or live shortened and debilitating lives. Research in the last few decades has taken gene therapy from a dream to a reality in the treatment of human disease.

Works Cited:

1. What is gene therapy? Genetics Home Reference, National Institutes of Health. 2017;

2. Mukherjee S. The Gene, An Intimate History. New York, NY: Scribner; 2016.

3. De Ravin SS LL, Wu X, Choi U, Allen C, Koontz S, Lee J, Theobald-Whiting N, Chu J, Garofalo M, Sweeney C, Kardava L, Moir S, Viley A, Natarajan P, Su L, Kuhns D, Zarember KA, Peshwa MV, Malech HL. CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. Sci Transl Med. 2017(9):372.

4. Niemann Pick Disease Type C. National Organization for Rare Disorders. 2014;

5. Chandler RJ WI, Gibson AL, Davidson CD, Incao AA, Hubbard BT, Porter FD, Pavan WJ, Venditti CP. Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1. Human Molecular Genetics. 2016:ddw367.

6. Familial lipoprotein lipase deficiency. Genetics Home Reference, National Institutes of Health. 2017;

7. uniQure. 2017;

Cite This Article:

Peacock E., Chan G., Palczewski K., Lewis K., Ho J. Gene Therapy: Bringing Hope to the Rare Disease Community. Illustrated by P. Taarea. Rare Disease Review. March 2018. DOI:10.13140/RG.2.2.30757.19680.

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