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Pharmacodynamic pre-clinical studies

NRP compoundIn our view, the NRP lead compound and its parental chemical derivatives possess high efficacy and potency for the following animal models mimicking the human neurodegenerative diseases:

Refractory epilepsy in childhood / adolescence (Lennox-Gastaut Syndrome or LGS)

CuroNZ has shown very strong bioactivity for NRP2945 by completely abolishing convulsive seizure activity in the somatosensory rat cortex after intoxication with pentylenetetrazole (PTZ acute model) by simultaneously enhancing gene and protein expression relevant to the GABAergic pathway.

There is currently no specific animal model for LGS available but CuroNZ has now started to test NRP2945 in chronic, genetically-induced seizures models like GAERS and WAGrij rats mimicking absence seizures that are highly relevant for children diagnosed with LGS. We are currently testing NRP2945 at the Royal Melbourne Hospital (Assoc Prof Nigel Jones) for acute and chronic efficacy in conjuction with spatial memory and depression testing. Positive data will enable CuroNZ to prepare a data package to file for orphan drug destination later in 2016.

Motoneurone Disease

Motoneurone Disease with its most common form of amyotrophic lateral sclerosis (ALS) is a rare disease with a prevalence rate of 2 in 100,000 persons.

Causalities or strong hypotheses for the susceptibility to develop Motoneurone Disease are mainly unknown and only 2% of the patient population has inherited familial ALS with mutations/polymorphisms within their superoxide dismutase (SOD-1) gene region. This enzyme is one of the major anti-oxidant players in the human body.

The 90% patient group with unfamilial ALS have no current known genetic risk factors.

Animal Models

The best validated animal model mimicking familial ALS is the G93A gain of function SOD-1 mouse mutant model.

The only FDA-approved drug Riluzole shows significant survival-promoting effects in this mouse model.

New drug approval applications are looking for combinational effects of new drugs showing synergistic effects compared to Riluzole alone.

NRPs show the following results in the animal model:
  • NRP dosages within a range of factor 100 apart are efficacious.
  • NRP dosages of ng/kg to μg/kg range are effective in the SOD-1 mouse model

Peripheral Neuropathy

active healthy neuronePeripheral neuropathy (PN) is a peripheral nervous system condition that is associated to diseases like HIV where anti-viral compound induced toxicity leads to PN.

The biggest group of sufferers derives from diabetes patients as well as from chemotherapy-treated cancer patients.

One of the micronutrients responsible to prevent PN in the body is the pro-drug pyridoxine that is converted by the liver to vitamin B6 that is used as co-enzyme for various biochemical reactions in the body.

The daily recommended intake for humans is 1-2mg /kg bodyweight.

Paradoxically, long-term daily dosages of 100-150mg/kg lead to the development of reversible neuropathy as being felt in the extremities.

Big diameter nervous endings in the skin are affected and diminished over time causing moderate to severe neuropathic pain.

Animal Models

An animal model that is mimicking such condition is the megadosage pyridoxine rat model.

Animals injected with megadosages of pyridoxine show severe motor impairments at the height of pyridoxine blood levels (8 days after start of intoxication).

Severely intoxicated animals cannot perform easy tasks like beam walking because of severe balancing problems.

So far, known efficacy is shown by the application of the nervous growth factor neurotrophin-3 that is effective when given daily at a 15mg/kg peripheral dosage.

NRPs show the following results in the animal model:
  • NRP dosages within a range of factor 100 apart are efficacious.
  • NRP dosages of ng/kg to μg/kg range are effective in the megadose pyridoxine (pdx) rat model (800mg pdx/kg/day for 8 days)
  • NRP prevents death in the μg/kg range within the ultra-high megadose pyridoxine rat model (1200mg pdx/kg/day for 5 days)

Multiple Sclerosis

The disease Multiple Sclerosis (MS) is the most frequent of the de-myelinating central nervous system conditions and is more common in acclimated climate zones.

Differential vitamin D-dependent metabolism effects have been strongly implicated in the prevalence of the disease. Nevertheless, currently there is no direct link between environmental and/or genetic traits that can predict susceptibility to MS.

treatments for MSThere are different forms of disease severity, including relapsing-remitting disease patterns, secondary progressive MS and primary progressive MS.

Various drugs like interferons, glatiramer acetate, mitoxantrone and the humanized anti-integrin receptor antibody (natalizumab) directed against the central nervous system (CNS) invading immune cells have been approved.

There is no treatment available for the most debilitating form of the disease, namely primary progressive MS.

All available therapeutic approaches aim to reduce relapse rates of the disease putting a clear emphasis on the control on the anti-inflammatory side of the immune system.

No approved drug provides a therapeutic impact regarding the repair of previously damaged CNS (e.g. reduction of existing MS plaques that represent areas of largely de-myelinated regions with ruptured electrical connections).

There is unmet medical need for CNS-regenerative therapies within the more severe and progressed forms of MS.

Animal Models

One animal model mimicking severe MS is the experimental autoimmune encephalitis (EAE) mouse model using the antigen MOG as the immunising agent.

  • Disease is induced by repeated injection of a protein that is part of the electrically insulating fat/protein layer of the nervous fibre.
  • Mice develop severe forms of paralysis and tetraplegia coinciding with a strong autoimmune response against the nervous fibre insulation.

The FDA-approved drugs show various beneficial activitieslarge molecule when applied in a prophylactic manner to the EAE mice while therapeutic treatment (start of drug administration at the height of disease) do not show significant beneficial effects.

The drug erythropoietin (EPO) reveals the highest beneficial effects during EAE therapeutic treatment.

However, disadvantages of EPO are its large molecular size that makes peripheral administration strategies challenging and its strong side effects on immune and blood cell generation.

NRPs show the following results in the animal model:
  • NRPs are highly effective in the lower μg/kg range in EAE mice
  • Strong effects in prophylactic and therapeutic applications
  • Peripheral IP injection is the preferred route of administration

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