Snapshot: What are Clinical Trials

How does a medical drug get to patients?

Research is being done every day to discover new or better ways to treat diseases and various medical conditions. In order to determine if these treatments will help patients, studies known as “clinical trials” need to be done before these methods of intervention can be safely and widely used in human patients. Clinical trials are regulated studies that involve volunteer human participants to test how safe and effective a potential new treatment.

doctor writing notes
Physician writing clinical notes. Photo by Pexels

Treatment interventions being tested can range from medical drugs, to medical devices, to introducing lifestyle changes (diet, exercise). Most clinical trials test new drugs by comparing them to no treatment, to an inactive version of a drug known as a “placebo”, or to a currently available approach. Clinical trials may take months to years to complete and are conducted in a series of steps, known as “phases”, described below.

Phase 1: Is the drug safe?

Healthy volunteers receive different doses of the drug and side effects are evaluated. Safe doses are chosen based on research performed prior to Phase 1, or “pre-clinical research”. The goal is to make sure the drug is not harmful. Usually lasts a few months.

Phase 2: Is the drug effective?

Similar to Phase 1, but the drug is given to a small group of volunteers affected by the medical condition it is intended to treat. This is commonly done by comparing how well participants do with the new drug compared to a placebo. Participants and doctors are typically “blinded”, or prevented from knowing whether the patient received the active drug or the placebo. This is meant to allow for unbiased observations of the participant’s health in response to the drug. Usually lasts a few months to years.

Phase 3: Is the drug still safe? Is it doing what is needed?

Testing becomes a bit more complex. The participant population is expanded while safety and efficacy of the drug continues to be tested. More detailed information about the drug as a treatment is gathered in this phase. Usually lasts several years.

Phase 4: The drug is approved and available on the market.

Long-term effects of the drug will continue to be monitored by pharmaceutical companies and compared to other available drugs and therapies for cost and efficacy.

If you would like to learn more about clinical trials, take a look at these resources by ClinicalTrials.gov and CenterWatch.

Snapshot written by Dr. Claudia Hung edited by Dr. Judit M. Perez Ortiz.

 

 

Snapshot: What is an antisense oligonucleotide (ASO/AON)?

Antisense Oligonucleotides (also known as ASOs or AONs) are small molecules that can be used to prevent or alter the production of proteins. Proteins are the workforce of the cell, taking care of most cellular processes. They are generally made in a two-step process: first, a specific protein-coding gene is converted into an instruction file, called the messenger RNA (mRNA). The mRNA carries the information from that gene to the compartment of the cell that builds proteins. There, the mRNA’s information then gets converted into the protein. ASOs are short single stranded pieces of DNA that match the complementary sequence of a specific mRNA. Based on the type of chemical modifications, the ASO can have two different effects on the mRNA. Some modifications of ASOs trigger the destruction of the mRNA. This will result in the loss of the corresponding protein. Other modifications can mask only certain parts of the mRNA leading to a modified version of the protein.

diagram showing how ASOs can bind or snip mRNA to create alternative forms of protein or prevent protein synthesis
How ASOs work in the human body. Image by Larissa Nitschke, Created with BioRender.

The majority of Spinocerebellar Ataxias (SCAs) are caused by the accumulation of toxic proteins in certain regions of the brain. The primary goal of ASO treatments for SCAs is therefore to prevent the production of the toxic protein altogether. One example is work from Dr. Harry Orr’s group at the University of Minnesota. His lab studies Spinocerebellar Ataxia Type 1 (SCA1), which is caused by the toxic accumulation of the Atxn1 protein. Injections of ASOs into a SCA1 animal model decreased Atxn1 levels and rescued the SCA1 motor incoordination symptoms. Another way of using ASOs as treatment for SCAs is the modification of the mRNAs information to produce a modified version of the protein. This approach has been tested in Spinocerebellar Ataxia Type 3 (SCA3), in which an expansion in the Atxn3 gene renders the Atxn3 protein toxic. The van Roon-Mom group from the Netherlands, for instance, used ASOs to only remove the expansion from Atxn3 while leaving the remaining protein structure and function intact.

Both studies as well as other studies performed for additional SCAs are highlighting the potential use of ASOs as therapeutics for SCAs. While ASO research for SCA is mostly in the pre-clinical phase, ASO treatment for other diseases, including Duchenne muscular dystrophy and spinal muscular atrophy, have already gained approval by the US Food and Drug Administration (FDA). Further clinical trials will need to be performed to measure the therapeutic benefit of ASOs in SCA patients.

If you would like to learn more about antisense oligonucelotides, take a look at this article in HDBuzz about ASOs in development for Huntington’s Disease.

Snapshot written by Larissa Nitschke edited by Dr. Hayley McLoughlin

 

 

Snapshot: What is an ion channel?

One of the most important features of neurons (Purkinje cells, for example), is that they are capable of electrical communication. Think of the last time you saw a TV intro or movie montage with a depiction of the brain on a microscopic level – though it’s technically invisible to the naked eye, that ‘spark’ you can see traveling down a portion of the neuron is actually not too far from reality. One of the most common ways to describe an active neuron, in fact, is to say that it’s “firing.” Essentially, when a neuron is activated, it ‘fires off’ an electrical impulse that is transmitted down a long, slender extension known as the axon. The axon ends where the next neuron in the circuit begins, and when the impulse arrives at that point, it initiates a series of events that allows the signal to jump to the next cell.

cartoon of neuron delivering an electrical impulse
An electrical impulse traveling down a neuron. Photo courtesy of Wikimedia.

This electrical signal is made possible by molecular machines known as ion channels. These proteins span the cell membrane, which is the barrier between the interior and exterior of the cell. When they receive a certain signal, the channel opens, allowing ions – atoms that carry an electrical charge, such as sodium, potassium, and calcium – to pass through. There are many types of proteins that allow the transport of small molecular components, but the source of a neuron’s electrical capabilities is that its channels specifically allow ions to pass into or out of the cell. Though a single ion’s charge is quite small, the large number of ions that are exchanged when a neuron’s channels open makes for a significant electrical effect – enough to produce an electrical signal that allows neurons to communicate with one another, giving us the ability to think, move, and interact with our environment.

diagram of an ion channgel in the closed, open, and inactivated state.
Cartoon of an ion channel in different states. Photo courtesy of Wikimedia.

Though the mutations that cause SCAs typically occur in genes that are expressed in every cell of the body, disease is usually restricted to the brain. One theory about why this is the case is that these SCA-related genes are necessary for the health and maintenance of ion channels in certain brain tissues – namely, the cerebellum and brainstem. At any rate, there is evidence that the electrical activity of these brain regions is abnormal in many SCAs, which strongly suggests that ion channels play a critical role in these disorders.

If you would like to learn more about ion channels, take a look at this Encyclopaedia Britannica article.

Snapshot written by Logan Morrison edited by Dr. David Bushart

 

 

Snapshot: What is Polyglutamine Expansion?

The information that allows the normal development and functioning of each human being is coded in DNA, which exists in all cells of the body. Several successive segments of DNA make up a gene, with the human body containing approximately 20,000. Every gene has a different arrangement of DNA segments and itself codes for a protein with a specific function. Genes code for proteins in the sequence of their DNA: combination of DNA sequences “code” for different protein precursors called amino acids. Thus, information from DNA (“genes”) codes for amino acids, which come together to form proteins, who function to maintain the normal well-being of the body.

A small number of genes have a small segment of DNA that is repeated successively, usually a couple dozen times, for unknown reasons. When the respective protein is formed, it also possesses a repetition of the same amino acid, corresponding to the repeated DNA segment. These repetitions in proteins have the prefix “poly”, meaning that the amino acids are repeated multiple times in a row, causing an “expansion” in the protein. One of the most common repeated amino acids is called glutamine: hence the name, polyglutamine.

Diagram showing how multiple CAG triplet repeats code for replicates of glutamine to be inserted into a protein
Photo courtesy of NHS HEE Genomics Education Programme.

When there is an increase in the number of repetitions of these segments in DNA, we say that an expansion of the polyglutamine has occurred. When the number of glutamines is increased sufficiently, a disease can develop: we call these disorders “polyglutamine diseases”. Some examples of diseases caused by this polyglutamine expansion are Huntington’s disease, SCA1, SCA2, SCA3, SCA6, and SCA7. The difference between all these diseases is that the expansion of the DNA segment that causes the polyglutamine occurs in different genes. Since these genes are distinct, the way that this expansion interferes with the normal body functioning is also different, giving rise to altered clinical presentations and courses. Moreover, it has been well established that, the larger the number of times that the segment is repeated, the more severe the disease will be. Finally, it has also been observed that throughout each generation, abnormally increased segments tend to become even bigger, making the disease worse.

The discovery of this mechanism of disease has been very important for scientists, since it allows for a “molecular diagnosis” of the disease. Armed with this understanding, research is now focused on understanding this process and finding ways to block the negative effects of polyglutamine expansion.

If you would like to learn more about polyglutamine expansion, take a look at this article.

Snapshot written by Jorge Diogo Da Silva, edited by Dr. Maxime Rousseaux

 

 

Snapshot: What is DNA?

DNA (deoxyribonucleic acid) is the way that living beings store the information that determines how they look and function. Think about DNA as the blueprints, or instructions, for life. All life forms – humans, cats, dogs, trees, and bacteria – all contain DNA. Your DNA is what carries the information that decides your specific traits, like what color eyes you have or if you will be tall or short. All the information in your DNA is unique to you. No one else in the world has the exact same DNA as you, unless you have an identical twin. You do share about fifty percent of your DNA with your biological parents, because the information stored in DNA is transmitted from generation to generation. This is why you look a little bit or a lot like your parents.

The reason that traits, like having blue eyes or being short, run in families is because they are transmitted in genes, which are the functional units of DNA.  Genes work on a very small scale, providing instructions to the cells of your body so they know what they need to make to do their jobs. While normal changes in the DNA can influence physical characteristics, like eye color, sometimes abnormal changes in the DNA may cause individuals to develop a disease. This is the case for hereditary ataxias. The abnormal DNA changes (called “mutations”) make it so cells no longer do their jobs well. Although we live with the same DNA information all our lives, it may take years or decades for a disease to manifest. As with genes for eye color, the genes causing a disease can be transmitted across generations. This explains why families are more likely to have relatives with the same type of ataxia.

Cartoon drawing of DNA moleculue next to an image of a ladder
Cartoon of DNA (Left), Photo of a ladder (right)

So, that is what DNA does, but what does it actually look like? DNA forms a double helix, think of it as a twisted ladder. The sides of the DNA ladder are made up of sugars, specifically “deoxyribose” units, and phosphate groups, and the rungs of the ladder are made up of bases. There are four bases, adenine, thymine, guanine, and cytosine, or A, T, C, and G for short. In the DNA ladder, each rung is made up of two bases forming a pair, either A and T or C and G. The instructions for life are “written” into our DNA using these bases, sometimes called the “genetic code”. The language of the genetic code has a lot fewer letters than our alphabet, just A, T, C, and G, but together these four bases write every instruction for every function and characteristic of every living thing that has ever existed in the form of genes.

If you would like to learn more about DNA, take a look at this BBC article.

Snapshot written by Dr. Laura Bowie, edited by Dr. Judit M Perez Ortiz.