Are Antisense Oligonucleotides and Effective Trearment for Huntington's Disease

Huntington’s Disease is a brain disorder affecting movement, cognition, and emotions (Schoenstadt). It is a genetic disorder generally affecting people in their middle 30s and 40s (Sheth). Worldwide, Huntington’s disease (affects between 3-7 per 100,000 people of European ancestry (Schoenstadt). In the United States alone, 1 in every 30,000 people has Huntington’s disease (Genetic Learning Center). Huntington’s Disease is a multi-faceted disease, with a complex inheritance pattern and a wide range of symptoms. There is also much research being done in the field of Huntington’s disease, because as of 2012, this disease is untreatable. THESIS.

The genetic disorder is caused by a mutation in the DNA segment CAG found in chromosome 4 which results nerve cell death. Phenotypic characteristics include gradual motor dysfunction, psychological issues that correlate to degeneration of metal health, and cognitive degeneration. Studies on transgenic mice have allowed a better understanding of the proteins that relate to Huntington’s

Huntington's Disease is a genetic autosomal disorder which effects the brain. It affects about 1 in 20,000 individuals. The symptoms of the disease do not start to occur until after or around 40 years of age. With the onset of the disease the patient starts to gradually deteriorate intellectually, this deterioration also causes involuntary movements. Scientists have only recently found the section of the gene which causes Huntington's disease, and this is allowed them to devise pre-symptomatic tests. However, a cure for the disease is yet to be found.

Huntington’s disease may be irreversible but it can be treated with proper treatment may slow down the effects of the disease and medical attention. In children who have symptoms of Huntington’s disease, some of the symptoms would be a rapid deteriorating in school performance, lack of swift movements, behavior changes etc...

Huntington's Disease (HD) is an autosomal dominant, progressive, neurodegenerative disorder (Walker, 2007 and Harmon, 2007). The gene that causes the disease is located on the fourth chromosome and causes an abnormal number of repeats in the patient's genetic code (Harmon, 2007). Huntington's Disease can have devastating effects on patients' quality of life. The first symptoms of HD generally start between the ages of 30 and 45 and patients are typically asymptomatic prior to this time (Terrenoire, 1992 and Walker, 2007). However, the disease progresses with subtle changes in motor control, personality, and cognition. Patients eventually develop distinct

At present, there is no cure for the disease, but dynamic progress has been made as researchers explore this illness. HD is inherited as an autosomal dominant condition. In March 1993, scientists realized that HD is caused by a mutation in a gene located on chromosome 4. This gene has a unique genetic sequence for CAG (cytosine-adenine-guanine) and codes for the amino acid glutamine, a building block for the huntingtin pr otein. Normal individuals have this sequence duplicated from 11 to 40 times in their genetic coding without having symptoms of HD. However, individuals with the disease have from 40 up to 100 repeated CAG segments. Juvenile Huntington's Disease occurs wit h 60 or more repeats, linking the longer chains of CAG sequences to earlier and more aggressive onset of the disease.

Huntington’s disease is an autosomal, dominant inherited disorder caused by a polyglutamine expansion at the amino-terminal on the huntingtin protein. It causes a progressive degeneration of spiny nerve cells in the striatum and cortex of the brain, impairing a person’s functional and cognitive abilities. Polyglutamine repeats of 36 are found to be non-threating but sequences containing an additional two or three repeats are associated with Huntington’s disease.

4. “Huntington Disease - Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/huntington-disease.

Huntington's disease is an autosomal dominant disorder, which is found on the # 4 chromosome. George Huntington discovered it in 1872. It mainly has an effect on the nervous system. There are around 210,000 bases between D4S180 and D4S127. The disease itself is found in 2% of people in their childhood, and in 5% of the people they were older then 60. (Miller p 16) In the majority of the affected people the disease is detected between the ages of 35-45. In males the disease begins around the time of their childhood. However, in females it begins later in life. This severe symptom has a tendency for the condition to worsen as it is passed on from generation to generation. Huntington’s disease is paternally

Uncertainty, the cause of stress and worry for people of all ages, is incontrovertibly a dreadful and uncomfortable feeling. Fear of the unknown affects everyone, whether it results from something as inconsequential as a quiz grade or the possibility that an fatal disease exists within your DNA. However, the anxiety caused by uncertainty is infinitesimal compared to the excruciating pain that the certainty of a humiliating and agonizing death can bring, especially to those who have not yet had a chance to live. Huntington’s is a disease that leads inevitably to this death, and there are many people in the world who believe that they may have it. A genetic test is available to confirm the existence of the disease within an individual’s genome,

Treatments have traditionally been target at specific symptoms that are present. Mexilentine has been shown to be effective in treating myotonia in patients with DM1 and is well tolerated with no serious complications(Logigian, Martens et al. 2010). Implantation of a pacemaker in patients with HV interval > 70 ms even when asymptomatics seems to be protective against sudden death due to arrthymia such as atrioventricular block(Lazarus, Varin et al. 2002). The cure for DM1 ultimately lies in targeting the underlying molecular causes. Antisense oligonucleatide have been synthesized against the mutant DMPK allele. PS58, a 2’-O-methyl phosphorothioate modified (CAG) 7 oligo has been shown to be effective in selectively reducing the level of the expanded CTG DMPK allele (with little effect on the normal allele) in vitro in myocytes derived from DM1 patients and in vivo in DM1 model mice(Mulders, van den Broek et al. 2009). The further development of these ASO to eventual clinical trials will hopefully lead to cure for

I chose this article because it characterizes the transduction profiles of a variety of AAV vectors that cross the blood brain barrier and transduce cells throughout the CNS. I am particularly interested in this gene delivery strategy – especially as it may apply to clinical therapeutics for Huntington’s disease (HD), a genetic neurological disease that causes widespread degeneration throughout the CNS. I spent the last few years working on studies that characterized the transduction profile of AAV9 in the CNS and periphery in a mouse model of HD. The aims of these studies were to: 1) Assess whether or not AAV9 has a tropism for the specific peripheral tissues and CNS regions that are affected in HD; 2) Evaluate whether systemic delivery using an AAV9 vector would be suitable delivery strategy to deliver an RNAi construct that could reduce HD symptoms. Accordingly, by choosing this paper, I was hoping to build a better understanding of other AAV vectors (in addition to AAV9) that cross the blood brain barrier and potentially could be used for vascular delivery of an RNAi construct throughout the CNS.

Huntington’s disease is a neurodegenerative disease that is procured from a repeat expansion of CAG in chromosome 4 the Huntington’s gene. “When the number of CAG repeats passes 39 then the disease will inexorably occur at some point in life” (Cepeda). Scientists currently do not know for certain why the cells within the basal ganglia specifically die in Huntington’s patients because the huntingtin protein is present is all cells not just exclusively nerve cells. The normal function of the huntingtin protein is relatively unknown but it is necessary for growth and development and is active throughout the body. “The huntingtin protein undergoes a posttranslational modification, and some events like phosphorylation play a large role in helping

VOYAGER THERAPEUTICS, INC. is a growing Clinical stage Gene Therapy Company. The main focus of this company is based on developing life changing treatments for patients suffering from various types of disease associated with central nervous system or CNS. The gene therapy is called AAV or adeno-associated virus, which is a therapeutic approach to alter the expression of a specific protein, thereby reducing the symptom experienced by patients, and that, will have a clinically meaningful impact on the patient’s life. The company has created a product engine to engineer, optimize manufacture and deliver AAV based gene therapy which would have a sustainable efficacy that follows a single administration directly to the CNS. The product engine has launched a program to address the underlying cause or the predominant manifestation of CNS disease which includes five most common CNS indications; Parkinson’s disease, Friedreich 's ataxia, Huntington 's disease, spinal muscular atrophy, and Multiple, sclerosis.

Abstract: Although Anti-sense Therapy has limitations related to targeted drug delivery, it is still considered as one of the promising technology for treating most of the Rare and Inherited disorders, being categorized as precision medicine has advanced very much with recent advances in drug delivery technologies like lipid nanoparticle (LNP) formulations, cell-targeting technologies. Anti-sense drugs are seen as most potential drugs for treating debilitating conditions with more targeted approach. The journey of Anti-sense oligonucleotides from the state of highly potential drug candidates to a sudden debacle with limitations in drug delivery and toxicity and the resume of these candidates with technological advancements will be reviewed with a special focus on application of this technology for the treatment of Huntington’s disease and spinal muscular atrophy. The most recently accepted application of Nusinersen, an anti-sense oligonucleotide drug for spinal muscular atrophy by US FDA and EMA and many candidates in late stage clinical trials proves the viability and glory of these candidates as potential drugs for treatment of rare diseases and conditions that need more targeted approach.