Hope on the horizon for HUNTINGTON’S

No question about it, Huntington’s disease (HD) is cruel. In the beginning, sufferers of this fatal neurodegenerative disorder experience involuntary movement and mood disturbance, most often in the form of depression. As the disease progresses, patients lose the ability to walk, speak, and eventually even swallow. Life expectancy after symptoms first appear is about twenty years. Ninety percent of HD cases affect adults between the ages of 30 and 50. The remaining ten percent of patients are even younger, and the course of their disease faster.

As if to recognize Huntington’s Disease Awareness Month (each May), there is some good news for Huntington’s sufferers and their loved ones. Last week, Roche (Basel, Switzerland) and Ionis (Carlsbad, CA) scientists published a paper describing their promising Phase I/IIa study of a new Huntington’s drug temporarily labeled RG6042. The study demonstrated that the new drug is safe. Researchers also observed some preliminary signs of efficacy in the small number of participants tested. 

Larger, more extensive tests are required before anyone can definitively say that the drug works. But even this small study provides hope in the face of this devastating disease.

This week, we review the basics of nervous system function and explain Huntington’s disease in more detail. Then we’ll describe the Roche treatment and others in development.

The Body Electric

Our nervous system is incredibly complex. It stretches into the body’s every nook and cranny, controlling and receiving all of the outside world’s signals from a central command station. Like any other part of us, the central nervous system (CNS) falls prey to diseases we don’t always understand.

The CNS—the brain and spinal cord—works with the peripheral nervous system. This vast network feeds into every tissue and funnels data to central command. The signals received from nerve cells enable both voluntary and involuntary movement. They also allow the brain to process and interpret sensory information.

Specialized cells called neurons convert chemical messages into electrical signals that convey information throughout the nervous system. Dendrites, branch-like structures, take in chemical messages down through the cell body (soma). The long, tail-like extension on the other end of the neuron is an axon. They are insulated by a fatty membrane known as a myelin sheath. This protective coating also helps speed electrical signals through the axon terminals.

Neurotransmitters are data delivery guys. They are chemical messengers that work in the spaces in between neurons, the synapses. When the neuron’s dendritic branches encounter a neurotransmitter, ion channels in the neuronal cell membrane open. These minute gaps allow positively charged sodium ions to enter a cell. The positive charge initiates an electrical signal through the neuronal body and down the axon tail, releasing other neurotransmitters into a neighboring synapse. This process creates a cascade of neurotransmitters down the neuron chain, with different neurons sending and receiving different neurotransmitters.

The billions of neurons within the CNS—communicating via hundreds of different neurotransmitters—regulate just about everything: our movement, hunger, temperature, emotion, and arousal. Everything!

Slow Killer In Action

Huntington’s Disease is an attack on this electric power grid. It’s monogenic, caused by a mutation in one gene—the huntingtin gene. The disease is also autosomal dominant: if one parent has HD, their children have a 50 percent chance of getting it. Because the disease has no cure, some at-risk individuals struggle over whether to test for the gene. Unless symptoms of juvenile-onset HD are present, testing for HD before age 18 is prohibited. The intent of the restriction is to help ensure those tested more fully understand the implications for their future.


The mutation that causes HD is a trinucleotide repeat. Three nucleotides (CAG) are repeated in the middle of huntingtin gene (HTT). Even normal versions of HTT have the CAG trinucleotide repeat. However, fewer than 36 repeats means the disease is not present. Higher than 40 means the disease manifests; 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. (Article continues below)

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RG6042 Mechanism Of Action

RG6042 is an antisense drug, This approach aims to reduce how much protein a specific gene produces—in this case, the mutated huntingtin gene. RG6042 operates by destroying the gene’s RNA.

Recall that the information in genes is first converted to RNA, which is then translated to a protein. This approach works on the premise that impeding the production of mutated huntingtin will result in fewer of HD’s heartbreaking symptoms.

Antisense therapeutics utilize existing cellular pathways that target and destroy double-stranded RNA (dsRNA).To activate the pathway, researchers introduce a piece of modified RNA with a sequence that complements the mutated huntingtin RNA. With RG6042, this synthetic RNA is the drug. Because its sequence is complementary to the mutated huntingtin RNA, this new drug binds it. The cellular enzyme RNAse H then cuts up the RG6042/mutated huntingtin RNA hybrid. No mutated huntingtin RNA, no mutated protein.

In the Phase I/IIa trial, patients exhibited reduced amounts of mutated huntingtin protein in their spinal fluid.

Other Drugs In Development

Until recently, the function of HTT and how its mutations 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 the protein PPARδ. The protein’s function is significantly diminished in HD neurons, possibly because of interaction with the mutated HTT protein.

Researchers identified an experimental drug, KD3010, as boosting PPARδ activity. This product was tested in a mouse model of HD and found to significantly reduce neurodegeneration. Even better news—the drug has already passed human safety trials for diabetes. That will likely speed KD3010 trials for HD.

Because HD is a single gene disorder, it makes a good candidate for gene therapy and genome-editing approaches. Sangamo Therapeutics (Richmond, CA) is conducting preclinical research on zinc-finger mediated genome editing in HD.

Huntington’s disease is a formidable opponent for both its sufferers and the health care professionals struggling to help them. These latest technologies might just be powerful enough make a difference.

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