THE PRIMER

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 even swallow. Life expectancy after symptoms first appear is about twenty years. Ninety percent of HD cases affect adults between 30 and 50. The remaining ten percent of patients are even younger, and the course of their disease is faster.

Reflecting on Huntington’s Disease Awareness Month this May, the 2023 campaign highlighted the significant impact of cognitive impairment on those with Huntington’s, their families, and caregivers, reinforcing the importance of early intervention and understanding of the disease; there is good news for people living with Huntington’s and their loved ones. In April 2020, 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. RG6042, also known as RO7234292 completed Phase III clinical trials for HD in March 2022 and tested its long-term safety and tolerability in HD patients. 

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.

In this article, we will 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.

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Our nervous system is incredibly complex. It stretches into the body’s every nook and cranny, controlling and receiving 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). An axon is the long, tail-like extension on the other end of the neuron. 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 between neurons, and 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 various 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!

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 restriction intends 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 the huntingtin gene (HTT). Even normal versions of HTT have the CAG trinucleotide repeat. However, fewer than 36 repeats mean the disease is not present. Higher than 40 means the disease manifests; copy numbers between 36 and 40 mean the individual may or may not be affected. Generally speaking, the higher the number of repeats beyond 40, the earlier the disease onset occurs and the more quickly HD progresses.

RG6042 is an antisense drug, and 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 HD’s painful 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 initially developed by Ionis Pharmaceuticals and later on acquired by Roche. 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, which is now being tested in Phase III clinical trial.

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 at Kalypsys identified an experimental drug, KD3010, as boosting PPARδ activity. This product was tested in a mouse model of HD and was found to reduce neurodegeneration significantly. Even better news—the drug has already passed human safety trials for diabetes. That will likely speed up 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) conducts preclinical research on zinc-finger-mediated genome editing in HD.

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

Huntington’s disease has historically been a daunting diagnosis, marked by debilitating symptoms and ineffective treatments. However, the horizon is brightening with the advent of promising drugs like RG6042 and KD3010. Coupled with ongoing research into gene therapy and genome editing, the future holds hope for HD patients and their families. As science delves deeper into the intricacies of HD, the global community looks forward with optimism, believing that solutions to conquer this disease are within reach.

1. WHAT IS HUNTINGTON’S DISEASE (HD)?

Huntington’s disease is a fatal neurodegenerative disorder that impacts movement, mood, and overall cognitive function.

2. AT WHAT AGE DO MOST PEOPLE DEVELOP SYMPTOMS OF HD?

Around ninety percent of HD cases affect adults between the ages of 30 and 50.

3. WHAT IS THE SIGNIFICANCE OF THE RG6042 DRUG?

RG6042, developed by Roche and Ionis, offers a promising treatment for HD by targeting the mutated huntingtin RNA, thereby reducing the production of the mutated huntingtin protein responsible for HD symptoms.

4. WHAT IS A TRINUCLEOTIDE REPEAT IN THE CONTEXT OF HD?

The mutation causing HD is a trinucleotide repeat, where three nucleotides (CAG) are repeated in the huntingtin gene (HTT). A higher number of repeats often leads to earlier disease onset and faster progression.

5. ARE THERE OTHER POTENTIAL TREATMENTS FOR HD IN DEVELOPMENT?

Yes, there are other drugs in development. For example, KD3010 targets PPARδ activity to combat neurodegeneration, and Sangamo Therapeutics is researching genome editing in HD.

6. WHAT IS THE PROGNOSIS FOR THOSE WITH HD?

Life expectancy after the onset of HD symptoms is approximately twenty years. However, emerging treatments and research provide hope for better outcomes in the future.

7. CAN CHILDREN GET HD?

Yes, while most cases affect adults, about 10% of patients are younger, and their disease progression is often faster.