Huntington’s disease is an inherited disorder that results in the death of brain cells, which consequently causes uncontrollable movements and serious cognitive problems (1). It has been estimated that about 3 to 7 in 100,000 people of European descent are diagnosed with Huntington’s disease. Despite the fact that there is currently no cure for Huntington’s disease, gene therapy has shown some encouraging results and is expected to improve the quality of life for patients with this genetic disorder (1).
A Neurological Disease
Even though Huntington’s disease was first described in 1872, then known as Huntington’s chorea, its cause has only recently been discovered (2). A gene mutation (inherited from the parents in almost all cases) in either of the two alleles is enough to cause the disorder. This autosomal dominant mutation affects the structure of the expressed Huntington protein (HTT).
The role of the HTT protein is not yet fully understood. However, science has shown that it is involved in many metabolic pathways, ensuring that it interacts with a vast number of other proteins. Studies have also proposed that HTT is crucially responsible for neuronal transcription and neurogenesis, and that it performs a very important role in embryonic development (3).
The phenotypic alteration of the HTT protein occurs due to the expansion of the cytosine-adenine-guanine triplet (CAG) that repeats in the gene, leading to the synthesis of the abnormal protein. While twenty-six or fewer CAG repeats is considered normal, patients with Huntington’s disease have many more repeats, which results in a defective gene (3).
The misfolded protein can affect cells in different areas of the brain, such as the neostriatum, the hypothalamus, and the cerebellum, among others. Aggregation of the mutated HTT protein unavoidably forms inclusion bodies that disrupt the normal neuronal networks, resulting in many alterations and progressing to dementia and other severe pathological complications (4). Technology that is used to measure protein interactions has revealed that the mutated HTT gene also interacts with caspase (an enzyme that catalyzes apoptosis) and alters its normal functioning. In addition, it interferes with the activity of chaperone proteins that assist protein folding (4).
As Huntington’s disease progresses, the symptoms often worsen. Some symptoms, in the initial phase, are similar to the ones manifested by patients with Parkinson’s disease. Slight uncontrollable movements are followed by many psychomotor complications. Although HTT is primarily found in the brain, its expression occurs in all cells. Thus, abnormalities in peripheral tissues — like muscle atrophy, osteoporosis, and cardiac failure — can also take place (1).
Gene Therapy: A Promissory Future
Life expectancy for patients with this all-consuming disease ranges from about 15 to 20 years after diagnosis. As there is no known cure for Huntington’s disease, countless treatments and therapies are being employed and tested to palliate the signs and symptoms (5). Tetrabenazine, which works as a dopamine-depleting agent, is undoubtedly the most popular medication administered to reduce the psychomotor complications. Neuroleptic drugs are also employed in patients with high tolerance to tetrabenazine (5).
Application of gene therapy to some neurological disorders is rapidly growing. Research is focused on developing small RNA fragments that can be used to suppress dominant-negative genes (6). Alternative routes and vectors to specifically distribute the transgene in the brain or the affected tissues are also being studied. Although there have been positive results in animals, finding the right vectors for humans still represents a major challenge (6).
Gene therapy AMT-130, which consists of an adeno-associated virus carrying an artificial microRNA, has achieved preclinical proof-of-concept. More efforts need to be made in order to develop a suitable treatment (7).
Undoubtedly, gene therapy is no longer given the backseat in the treatment world and appears to be the front-running solution to many neurological disorders like Huntington’s disease.
- Chaganti S, McCusker E, Loy C.. What do we know about Late Onset Huntington’s Disease?. J Huntingtons Dis. 2017; 6(2): 95–103. Published online 2017 Jun 30. doi: 10.3233/JHD-170247
- Mason R, Giorgini F. Modeling Huntington Disease in Yeast. Prion. 2011 Oct-Dec; 5(4): 269–276. Published online Oct-Dec 2011. doi: 10.4161/pri.5.4.18005
- Southwell A, Patterson P. Gene Therapy in Mouse Models of Huntington Disease. Neuroscientist. Author manuscript; available in PMC 2011 Jul 7. Published in final edited form as: Neuroscientist. 2011 Apr; 17(2): 153–162. doi: 10.1177/1073858410386236
- Simonato M, et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol. Author manuscript; available in PMC 2014 Jan 31. Published in final edited form as:Nat Rev Neurol. 2013 May; 9(5): 277–291. Published online 2013 Apr 23. doi: 10.1038/nrneurol.2013.56
- Aguiar S, Van Der Gaag B, Loy C. RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA. J Huntingtons Dis. 2017; 6(2): 95–103. Published online 2017 Jun 30. doi: 10.3233/JHD-170247