Huntington's disease clinical research
Encyclopedia
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
is a genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no cure or effective treatments. Animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s help in the ongoing investigations using intrabody therapy, gene silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
, or stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
implants, but all are at their first steps. Several clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s of various compounds are also in development. Many of these trials use the unified Huntington's disease rating scale (UHDRS) developed by the Huntington's Study Group. This provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, backed up by a reference database of previous results provided by HSG for reference. Another avenue of research is understanding the physical mechanics of protein folding, HD is one of several targets of the folding@home
Folding@home
Folding@home is a distributed computing project designed to use spare processing power on personal computers to perform simulations of disease-relevant protein folding and other molecular dynamics, and to improve on the methods of doing so...
project, one of the largest distributed computing
Distributed computing
Distributed computing is a field of computer science that studies distributed systems. A distributed system consists of multiple autonomous computers that communicate through a computer network. The computers interact with each other in order to achieve a common goal...
systems on the World Wide Web
World Wide Web
The World Wide Web is a system of interlinked hypertext documents accessed via the Internet...
.
Animal models
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
. Neurochemically-induced mice or monkeys were first available, but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome, of mice (strain R6/2),), Drosophila
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
fruit flies, and more recently monkeys. Expression without insertion of a DNA repeat in nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
worms also produced a valuable model.
Intrabody therapy
Genetically-engineeredGenetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
fragments called intrabodies
Intrabody (protein)
In molecular biology, an intrabody is an antibody that works within the cell to bind to an intracellular protein...
have shown therapeutic results, by inhibiting mHtt aggregation, in Drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment
Single chain variable fragment
A single-chain variable fragment is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins, connected with a short linker peptide of ten to about 25 amino acids...
which binds to the end of mHtt within a cell
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
. This therapy prevented larva
Larva
A larva is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle...
l and pupa
Pupa
A pupa is the life stage of some insects undergoing transformation. The pupal stage is found only in holometabolous insects, those that undergo a complete metamorphosis, going through four life stages; embryo, larva, pupa and imago...
l mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan. Intrabodies have shown promise as a useful tool for drug discovery
Drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
, and may potentially be used as a therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions
Protein interactions
Proteins can interact with many types of molecules. Such interactions are related to their function and are therefore an object of study in molecular biology, and of computational methods of prediction in bioinformatics.Protein interactions can be classified as:...
.
Gene silencing
As HD has been conclusively linked to a single gene, gene silencingGene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
is potentially possible. Researchers have investigated using gene knockdown
Gene knockdown
Gene knockdown refers to techniques by which the expression of one or more of an organism's genes is reduced, either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleotide with a sequence complementary to either an mRNA transcript or a gene...
of mHTT as a potential treatment. Using a mouse model, siRNA
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
therapy achieved a 60% reduction in expression of mHTT and progression of the disease was stalled. However, this study used the human form of the mHTT protein in mice, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
mouse Htt gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
unaffected. The widely-held hypothesis that silencing the wild type mouse Htt in middle aged mice, the age of onset of HD, renders undesirable, gene silencing to treat HD, is now largely discredited by experiment.http://www.ncbi.nlm.nih.gov/pubmed/19334076
- These data indicate that the coincident silencing of the wild-type and mutant htt may be considered as a therapeutic tool for HD.
This is despite the unchallenged experimental evidence that wild-type Htt is critical for development in mouse models. Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.
Stem cell treatments
Stem cell implants are a stem cell treatment where damaged neurons are replaced by transplantation of stem cellStem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, embryonic stem cell
Embryonic stem cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
s can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons; if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but stem cell treatment for HD remains highly speculative and has not been tested in clinical trials.
Pharmacological
, several trials of various compounds are in development or ongoing, a few at the point of testing on larger numbers of people, known as phase III of clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Substances that have shown promise in initial experiments include dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
receptor blockers, select dopamine antagonists, such as creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
and CoQ10, the antibiotic Minocycline
Minocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
, antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s such as sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
, fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
. In 2010, minocycline was found to be ineffective for humans in a multi-center trial.
A 2009 study suggested strong association between specific single nucleotide polymorphisms alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.
Other
Recently it was shown that increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.External links
- "Clinical Trials"-article on the Huntington's Disease Society of America website.
- "Studying HD"-types of research used to study HD on the Huntington's Disease Outreach Project for Education at StanfordHuntington's Disease Outreach Project for Education at StanfordThe Huntington’s disease Outreach Project for Education at Stanford is a student-run project at Stanford University dedicated to making scientific information about Huntington’s disease more readily accessible to patients and the public. Initiated by Professor William H...
website - "HDBuzz"- HDBuzzHDBuzzHDBuzz is a non-profit website that supplies news about Huntington's disease research in plain language.- Overview :HDBuzz was launched in January 2011 by Huntington's disease researchers Dr Ed Wild and Dr Jeff Carroll...
supplies the latest news about Huntington's disease clinical research, written by scientists in understandable language