Neurizon's NUZ-001 shows promise in Huntington's disease
Neurizon's NUZ-001 and active metabolite NUZ-001 Sulfone show strong neuroprotective effects in a zebrafish Huntington's model
Results show potential of drug to counteract early neurodegenerative damage caused by disease
Neurizon plans to initiate additional validation studies in mammalian models of Huntington's
Special Report: Clinical-stage biotech Neurizon Therapeutics has reached a milestone in development of its lead drug candidate NUZ-001 to treat Huntington's disease.
Neurizon Therapeutics (ASX:NUZ), which is dedicated to advancing treatments for neurodegenerative diseases, has rolled out new preclinical data demonstrating significant neuroprotective effects of NUZ-001 and its active metabolite NUZ-001 Sulfone, in a zebrafish model of Huntington's disease.
Huntington's disease is a rare, inherited neurodegenerative disorder that causes progressive degeneration of motor function, cognition and mental health.
The disease affects between 2.7 and 4.8 per 100,000 people globally with no cure and no disease-modifying treatment. The treatments available only manage symptoms.
In the Huntington's disease model, targeted mRNA knockdown of the Htt (huntingtin) protein triggered hallmark disease characteristics, including:
Increased cell death
Morphological malformations (smaller eyes and swollen hindbrains)
Impaired haemoglobin production and
Reduced expression of brain-derived neurotrophic factor (BDNF), a critical biomarker of neuronal function and survival.
mRNA knockdown is a lab technique that reduces the activity of a specific gene, in this case the HTT gene, which produces the protein involved in Huntington's disease.
Treatment with either NUZ-001 or NUZ-001 Sulfone after Htt knockdown:
Prevented developmental and morphological abnormalities
Attenuated neuronal cell death
Restored the delayed production of haemoglobin; and
Rescued BDNF expression.
Neurizon said the results provided evidence of NUZ-001 and NUZ-001 Sulfone's potential to counteract early neurodegenerative damage.
Study details
For the preclinical study, wild-type zebrafish embryos were raised in standard conditions.
Morpholino antisense oligonucleotides (MOs) targeting Htt mRNA were then injected into one-cell stage embryos to decrease Htt expression.
NUZ-001 or NUZ-001 Sulfone at 1 and 10 μM concentrations were added to the embryonic media six hours post-fertilisation to evaluate the protective effects on Htt knockdown-induced deficits.
At two days post-fertilisation changes in morphology (eye size and hindbrain swelling), neuronal cell death (apoptosis), haemoglobin levels, and the BDNF expression levels were analysed.
Source: Neurizon Therapeutics
Knockdown of Htt (Htt MO) resulted in smaller eyes and swollen hindbrain ventricles in zebrafish embryos.
Neurizon said partial rescue of eye size and full reversal of hindbrain swelling were observed with 10 μM NUZ-001 and NUZ-001 Sulfone (Figure 2b).
Source: Neurizon Therapeutics
Other key findings of the study include:
Neuronal cell death was significantly higher in the Htt knockdown group, while treatment with 1 μM and 10 μM NUZ-001, and 10 μM NUZ-001 Sulfone, significantly reduced apoptosis
Haemoglobin levels were significantly decreased in the Htt knockdown group but partially restored by both concentrations of NUZ-001 and NUZ-001 Sulfone; and
Expression of BDNF transcripts was significantly rescued with 10 μM NUZ-001 and 10 μM NUZ-001 Sulfone.
Watch: Last patient completes treatment in OLE study
NUZ-001 showing promise
NUZ-001 is currently in clinical development for the most common form of motor neurone disease (MND) called amyotrophic lateral sclerosis (ALS), where it has shown:
Preclinical efficacy in enhancing proteostasis
Reducing pathological protein aggregation; and
Preserving neuronal function.
The company said new findings in the Huntington model further underscore NUZ-001's potential as a platform therapy targeting core cellular stress and clearance mechanisms common to multiple neurodegenerative diseases.
Neurizon plans to advance additional preclinical studies in mammalian models of Huntington's disease as part of its broader strategy to expand NUZ-001's therapeutic applications to other progressive neurological disorders with high unmet need.
'These results mark another important milestone in the realisation of the potential for NUZ-001 to treat a range of neurodegenerative diseases,' CEO and managing director Dr Michael Thurn said.
'Huntington's disease is a devastating, rare genetic disorder that causes the progressive breakdown of nerve cells in the brain, leading to a range of symptoms including uncontrolled movements, cognitive decline, and emotional disturbances.
'These exciting results demonstrate NUZ-001 has consistent neuroprotective effects beyond amyotrophic lateral sclerosis (ALS), strengthening our conviction in NUZ-001's potential as a disease-modifying platform therapy across a range of neurodegenerative conditions.'
This article was developed in collaboration with Neurizon Therapeutics, a Stockhead advertiser at the time of publishing.
This article does not constitute financial product advice. You should consider obtaining independent advice before making any financial decisions.
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