Glossary

Axon extension of a nerve cell along which nerve impulses travel away from the cell body towards other cells. At the end of an axon there are axon terminals that may form specialized junctions called synapses – places where a nerve impulse is transmitted to another cell (e.g. neurons, muscle, gland cells).

Base a smaller molecular component of nucleotides, which make up DNA and RNA. There are four different bases - adenine (A), cytosine (C), guanine (G), and thymidine (T) - which are arranged in differing sequences in a DNA molecule. RNA molecules use uracil (U) instead of thymidine. The sequence of bases determines the instructions (genetic code) for the sequence of amino acids that form proteins.

Biomarker an indicator of a biologic state, disease process or drug response often used in drug development.

Carrier an individual that carries one gene for a trait but does not show the trait by itself. Offspring of two carriers could express the trait. In case of SMA, carriers do not show any symptoms of SMA and have one normal copy of SMN1 gene and one mutated, or defective, copy. Children of SMA carriers have 25% chance of inheriting 2 defective copies of SMN1 and have the disease. The presence of the defective copy of SMN1 gene may go unnoticed for many generations. Also see Autosomal Recessive Inheritance.

Cell the basic unit of the body. Cells are bound by a plasma membrane, and their cytoplasm-filled interior contains many organelles, including the nucleus and ribosomes, which allow the cells to carry out their specialized functions within the body.

Chromosomes structures within the nucleus of the cell that carry DNA. Humans have 46 chromosomes (23 pairs): a person inherits 23 chromosomes from each parent, namely 22 autosomal chromosomes plus an X or Y chromosome that determines gender.

Cytoplasm the interior, aqueous part of the cell, in which the organelles and inclusions are suspended. The cytoplasm is the site of important cellular activities, including cell division, many metabolic processes and protein degradation.

DNA (DeoxyriboNucleic Acid) a molecule composed of two chains of nucleic acid bases held together by hydrogen bonds in a pattern resembling a flexible twisted ladder. DNA is the core component of chromosomes, and contains the genetic instructions used by all living organisms and some viruses.

Drug Indication the FDA approved use of a drug.

Drug Labels FDA drug labels contain the name of the particular symptom, disease, or subset of patients within a disease that the drug is approved to treat, along with instructions for using the drug properly (including the dosage and what to do when a patient misses a dose), a description of any special instructions for taking the drug (such as with food or water), storage instructions, the symptoms of side effects to the drug, the names of any conditions or foods the patient should not have while using the medication, any warnings or precautions, any risk of drug tolerance or dependency, and a list of drug ingredients. The label also includes general instructions, like discussing questions with a health care professional, since the label is not intended to be all-inclusive.

Early Drug Development the phase of drug development in which synthetic small molecule compounds or biological molecules are identified and selected for further development as leads. This process typically includes assay development, high throughput screening, identification of “hits” that have activity in a test tube (or assay), characterization of hits and selection of leads for further optimization. The early drug development process often takes several years to produce drug leads.

ELISA (Enzyme Linked Immunosorbent Assay) a quantitative assay that employs antibodies to detect and measure the amount of a particular molecule in a fluid or tissue.

Exon a nucleic acid sequence that is present in the final RNA molecule after the splicing process edits the precursor RNA molecule. Precursor RNA (e.g. pre-mRNA) molecules have exon sequences interspersed with intron sequences; see intron.

Expression the process by which genetic information (DNA) is used to generate a gene product (RNA or protein); also known as gene expression.

Gene a region of genomic DNA sequence, corresponding to a unit of inheritance. Individual genes contain the instructions for making individual proteins. There are generally two copies of every gene, one on each paired chromosomes

Gene therapy a therapeutic approach in which engineered genes are introduced into a patient’s cells to treat a disease. Hereditary diseases like SMA maybe a prime therapeutic indications for gene therapy, where gene therapy will provide a functional replacement for a dysfunctional gene.

Genotype the genetic constitution of an individual, that is, the specific (allelic) makeup of an individual, usually with reference to a specific character under consideration. Often used with relation to phenotype, or the observed characteristics of expressed genes.

Hammersmith Functional Motor Scale (HFMS) a test battery developed by Main and colleagues, used to evaluate motor function and specifically developed for SMA Type 2 and 3 patients. There are multiple versions of the HFMS being used and validated, including the Expanded and Modified HFMS.

Incidence the frequency in which a disease or condition appears in a population, typically expressed as a percentage or ratio. For example the incidence of SMA births is approximately 1 in 6,000 – 10,000 babies.

IND (Investigational New Drug) a request to the Food and Drug Administration for authorization to administer an experimental drug or biological product to humans. This application precedes the start of human clinical trials.

Intron a nucleic acid sequence that is NOT present in the final RNA molecule after the splicing process edits the precursor RNA molecule (pre-mRNA); see Exon.

Label the FDA approved label is the official description of a drug product which includes indication (what the drug is used for); who should take it; adverse events (side effects); instructions for uses in pregnancy, children, and other populations; and safety information for the patient. Labels are often found inside drug product packaging.

Lead Optimization improvement of compounds that have been identified as ‘leads’ in early drug development. Lead optimization focuses on improving the pharmaceutical properties of compounds including efficacy, potency, exposure, safety, and stability in order to make them more drug-like. The goal of lead optimization is to identify a compound (Development Candidate) suitable for preclinical development.

Motor Neuron a type of nerve cell that conveys impulses from the central nervous system to a muscle or other effector tissue. Alpha motor neurons are a type of motor neurons responsible for innervation of skeletal muscle. Alpha motor neurons are located in the ventral horn of the spinal cord and are primarily affected in SMA.

Nucleic Acid a large molecule comprised of nucleotides. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

Nucleotide a subunit of DNA or RNA, composed of a base, a phosphate and a sugar molecule. Thousands of nucleotides are linked together to form the DNA or RNA sequence chains.

Nucleus the organelle within cells that contains the genetic material (DNA or chromosomes).

Off-Label Use a drug prescribed for conditions other than the indication(s) for which it was approved by the FDA.

Oligonucleotide a short nucleic acid polymer, generally of 25 or fewer nucleotides. Oligonucleotides can be made to complement DNA or RNA sequences (antisense oligonucleotides or ASOs) and can be used as therapeutics by influencing the expression of a target gene.

Onset the first appearance of signs and symptoms of a disease or condition.

Phase I Trials initial studies to determine the safety and pharmacologic actions of drugs in humans, and the side effects associated with increasing doses; in some cases can also be used to gain early evidence of effectiveness. Healthy participants and/or patients may be recruited for this phase of clinical trials.

Phase II Trials clinical studies conducted to evaluate the effectiveness of the drug for a particular disease or signs or symptoms in patients with the disease or condition under study and to determine the common short-term side effects and risks.

Phase III Trials expanded trials which take place after preliminary data from Phases I and II suggesting drug effectiveness has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug.

Phase IV Trials post-marketing studies designed to provide additional information including the drug's risks, benefits, and optimal use.

Phenotype an observable characteristic or trait of a cell or organism determined by the interaction of the genetic make-up or genotype and the environmental influences. The phenotype of SMA is proximal muscle atrophy and weakness.

Plasma the cell-free fluid component of blood that contains proteins, glucose, clotting factors, ions, and hormones.

Pre-mRNA (precursor messenger RNA) primary transcript produced from a gene during transcription. Newly synthesized pre-mRNA undergoes various modifications, one of which is splicing – removal of introns and joining the remaining exons.

Preclinical testing of experimental drugs, in the test tube or in animals, that occurs before trials in humans may be carried out.

Prevalence the total number of people in the general population with a particular disease or condition at any given time.

Promoter a region of DNA required for initiation of the transcription of DNA into pre-mRNA.

Protein the building blocks of cells - each protein molecule is composed of its own unique sequence of amino acids (there are 20 different kinds of amino acids in the human body).

Ribosome the large molecular complex ‘machines’ that translate the mRNA code into the amino acid chain that form proteins.

RNA (ribonucleic acid) a single stranded nucleic acid chain similar to DNA, which serves several important biological roles. Messenger RNA (mRNA) is the specific RNA sequence which is translated into an amino acid sequence that makes up a protein. Other types of RNA play important roles in regulating gene expression (microRNAs), RNA processing by the spliceosome (small nuclear RNAs or snRNA), and protein translation (tRNAs).

Small molecule a low molecular weight (usually less than 500 Daltons) organic compound that can bind to and alter the activity or function of proteins, nucleic acids, or polysaccharides. Most therapeutic drugs are chemically synthesized small molecules.

Spliceosome a complex of RNA and protein molecules that performs the splicing process on pre-mRNA.

Splicing the process by which introns are removed from the pre-mRNA molecules and remaining exons are joined together, forming the final messenger RNA (mRNA) that is translated into proteins.

Transcription the process by which pre-mRNA is synthesized from DNA resulting in transfer of genetic information from the DNA molecule into pre-mRNA. This process occurs in the nucleus.

Translation the process by which amino acid chains that form proteins are synthesized by ‘reading’ mRNA sequence as a template. This process is carried out by a multimolecular machine, the ribosome, and takes place in the cytoplasm.

Translational Research research spanning the activities from biological and drug discovery up to utility for patients – so-called “bench to bedside”. Generally refers to the process associated with developing a new treatment or drug.