Keeping the brain’s neurons alive under the many circumstances that lead to their demise is the critical goal of neuroprotection. Natural aging, neurodegenerative conditions, and trauma to the brain all lead to the death of neurons. The result is cognitive decline, memory failure, loss of motor coordination and, ultimately, death.
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Neuroprotection is needed in chronic conditions such as Alzheimer’s disease and cognitive impairment associated with schizophrenia, as well as acute disorders such as mild cognitive impairment (MCI) associated with post-cardiac artery bypass graft surgery (CABG), stroke and traumatic brain injury.
Figure 1: Alzheimer’s causes marked degeneration in the human brain
Figure 1: Alzheimer’s causes marked degeneration in the human brain
Neuroprotection may be used to prevent the progression of chronic diseases. It can be administered therapeutically following a central nervous system trauma to prevent secondary neuronal loss, or prophylactically prior to surgical procedures known to cause cognitive impairment.
Neuronal death is now understood to involve the same molecular mechanisms across many of these diseases and injuries. This pathway is known as programmed cell death, or apoptosis. It is likely that an agent that blocks fundamental steps in the mechanisms of apoptotic neuronal cell death will have multiple therapeutic applications.
Studies have shown that neuroprotection occurs as a natural response as the central nervous system responds to injury and involves altered gene expression and production of neurotrophic factors. However, in cases when the brain is suffering from external injury or disease, these natural mechanisms are inadequate, and external therapeutic intervention is required.
Allon’s portfolio of neuroprotective compounds, including AL-108 and AL-208, are derived from neuroprotective proteins that occur naturally in the brain.
Technology Background
Allon Therapeutics’s focus is developing neuroprotective therapeutic molecules. Allon’s drug candidates have been shown to work at the cellular level to protect or shield neurons from injury. They have been extensively validated in animal models of neurodegenerative diseases and trauma, are well tolerated and bioavailable.
Allon’s neuroprotective platform originated from studies on vasoactive intestinal peptide (VIP). VIP is a major central nervous system peptide that early studies showed to be a broadly-acting neuroprotectant. VIP was shown to exert its effects by causing neuroprotective proteins to be secreted from glial cells, also known as astrocytes (brain support cells). Activity-dependent neuroprotective protein (ADNP) and activity-dependent neurotrophic factor (ADNF) were identified as the proteins secreted by glial cells that provide neuroprotection in response to VIP. For ADNP, in addition to its neuroprotective efficacy, it was shown to be critical for brain formation. ADNP gene knockout mice do not form a brain during embryonic development and consequently die in utero.
Further research showed that an eight amino acid peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code NAPVSIPQ (NAP) derived from ADNP is able to confer the neuroprotective properties of the parent protein. AL-108 and AL-208, the company’s lead products are based on NAP. Similarly, a nine amnio acid peptide, Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro- Ala, SALLRSIPA (SAL, also termed ADNF-9) from ADNF is able to reconstitute the neuroprotective activity of ADNF.
Proprietary Compounds
Current therapies on the market address the symptoms of neurodegenerative conditions. Allon’s broad class of proprietary compounds treat the cause of these conditions by preventing neuronal cell death.
Allon’s compounds can be administered intranasally or intravenously. They cross the blood brain barrier, a selective filter that prevents many substances from entering the brain, and are delivered directly to the diseased area, showing activity and potency at low concentrations.
How Allon's Compounds Work
A common characteristic found in patients with neurodegenerative conditions is the death of neurons, which occur as a result of a breakdown of microtubules (cylindrical strands of protein that form a scaffold within the cell). When microtubules breakdown, the axonal transport within a cell and the chemical transmission between them is disrupted. This disruption causes neurons to die.
Allon’s compounds prevent neuronal cell death by interacting with neuronal tubulin, repairing the microtubular network as well as potentially restoring both axonal transport within nerve cells and chemical transmission between them. Allon’s compounds also promote neurite growth, which is dependent on microtubule formation. Numerous preclinical studies have shown that Allon’s compounds are safe and effective in treating a range of neurodegenerative conditions.
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