On The Hunt

In Biotech Basics, Drug Development, Drug Targets, Genetics, Genomics, Mechanism of Action, Orphan Disease, Orphan Drugs, Term of the Week, The WEEKLY by Emily Burke

The Hurdles Of Huntington’s

The nervous system is an incredibly complex piece of human machinery, stretching to the far reaches of the body while controlling and receiving the nuances of life from a central command station. Just like any part of the human body, the central nervous system (CNS) is affected by various diseases that are sometimes not entirely understood. After last week’s foray into the Alzheimer’s, we turn to investigate Huntington’s disease. Let’s catch up on the basics of the nervous system and find out what biotech has in the pipeline for this genetic neurodegenerative disease of the CNS.

Nervous System Primer

The CNS—which consists of the brain and spinal cord—works in tandem with the peripheral nervous system. The peripheral nervous system is the vast network of nerves feeding into every tissue of the body, the tentacles of data for the CNS. The signals received from nerve cells enable voluntary and involuntary movement, and allow the brain to process and interpret sensory information via the spinal cord.

Specialized cells called neurons convert chemical messages into electrical signals to convey data throughout the nervous system. The branch-like extensions are called dendrites, which work to take in chemical messages down through the cell body (soma). The long, tail-like extension on the other end is called an axon. They are enclosed in a fatty membrane known as a myelin sheath, which serves to insulate the axons and facilitate the passage of the electrical signal through the axon terminals.

Nerve Signaling

Neurotransmitters are data delivery guys and work in the synapse—the space between the neurons. When the dendritic branches of a neuron encounter a neurotransmitter, ion channels in the cell membrane open, allowing positively charged sodium ions to enter the cell. The positive charge initiates an electrical signal through the neuronal body and down the axon tail, causing the release of other neurotransmitters into the next synaptic break. This process creates a cascade of neurotransmitters to react down the neuron chain, with different neurons sending and receiving different types of neurotransmitters.Neuron SynapseThe billions of neurons within the CNS—communicating via hundreds of different types of neurotransmitters—regulate just about everything within the human body: from movement to hunger, temperature, emotion, and wakefulness.

Huntington’s Disease Explained

Like Alzheimer’s, Huntington’s disease (HD) is also a neurodegenerative disorder. Neurons progressively lose structure and function, get damaged and eventually die. Early stages may show subtle symptoms, such as involuntary movements and mood disturbances. As the disease progresses and more neurons die, the symptoms worsen. Sufferers of HD lose the ability to walk and speak, swallowing becomes more and more difficult. Life expectancy is about 20 years after the onset of initial symptoms. 90% of HD cases affect adults between the ages of 30 and 50; juvenile onset occurs in the remaining 10% of cases.

HD is monogenic, it is caused by a mutation in one gene dubbed the Huntingtin gene. The disease is also autosomal dominant, meaning if one parent has HD, their children have a 50% chance of getting it. There is currently no cure for HD and some at-risk individuals struggle with the choice to test for the gene. Unless symptoms of juvenile-onset HD are present, testing for HD before the age of 18 is prohibited to ensure those tested are old enough to understand the full implications of the disease.

Term of Week: Trinucleotide Repeat

The mutation that causes HD is known as a trinucleotide repeat, meaning the three nucleotides (CAG) are repeated multiple times in the middle of Huntingtin gene (HTT). Even normal versions of HTT have the CAG trinucleotide repeat, but fewer than 36 repeats means the disease is not present. Higher than 40 means the disease does manifest; copy numbers between 36 and 40 means the individual may or may not be affected. Generally speaking, the higher the number of repeats beyond 40, the earlier disease onset occurs and the more quickly HD progresses.

In The Pipeline

Until very recently, the function of HTT and how its mutations might cause neuronal cell death were largely unknown. Recent research from the University of California San Diego suggests that HTT plays a role in activating gene expression in neurons through its interaction with a protein known as PPARδ. PPARδ’s function is significantly diminished in HD neurons, possibly as a result of interaction with the mutated HTT protein. Researchers identified an experimental drug, KD3010, as one that actually increases PPARδ activity. KD3010 was tested in a HD mouse model and found to significantly reduce neurodegeneration. Even better news—this drug has already passed human safety trials as a potential diabetes treatment, so initiating HD trials of KD3010 could happen quickly.

Because HD is a single gene disorder, it is also a good candidate for gene therapy and genome-editing approaches. Sangamo Therapeutics (Richmond, CA) is conducting preclinical research on genome-editing in HD. Also in the mix is Ionis Pharmaceuticals (Carlsbad, CA) with their Phase II clinical studies of an antisense drug to block the production of the mutated HTT protein in HD patients.

The hurdles of Huntington’s disease are high, however, these latest technologies might just stand tall enough to make a difference.