The Science of Edunn

Our Product

Edunn is an early stage drug development company with an exclusive license to a novel class of central nervous system (CNS) drugs that shows promise in treating Alzheimer's disease (AD), Down syndrome, stroke and traumatic brain injury. These drugs, known as antisense oligonucleotides, are proven to cross the blood-brain barrier and thus can affect brain function. The company's initial focus is on development of EDN-OL1 to treat Alzheimer's.

Product Advantages

Currently available drugs for AD at best only slow the progress of the disease. In contrast, Edunn's first drug candidate, EDN-OL1 halts the progression of AD and improves memory and learning in 3 different Alzheimer's mouse models. Restoration of cognitive function in the three different mouse models occurs rapidly after only three doses of EDN-OL1. The rapid response is a distinguishing characteristic compared to competing drug candidates. EDN-OL1 works by reducing the production of the amyloid precursor protein (APP), the earliest step in the amyloid pathway. The large APP is cleaved by enzymes to yield a family of amyloid beta proteins (ABP) which are strongly implicated in the onset of Alzheimer's disease. Amyloid proteins are components of the plaque that is widespread in the brain of patients with AD. It is now understood that although plaque is damaging to nerve cells, the damage and toxicity caused by amyloid arises well before the plaque forms. It is also accepted that amyloid problems arise before the neurofibrillary tangles that are the second major feature of Alzheimer's anatomical pathology. Decreasing the amount of APP made in neurons in turn reduces the amount of ABP. In addition to AD, EDN-OL1 has shown promise for patients with Down syndrome.

Other advantages over current products on the market or in the pipeline include an established clinical safety record for this chemical class of drugs and convenient dosing at acceptable cost. A more recent discovery, EDN-OL202, has demonstrated potential for the treatment of stroke, traumatic brain injury, and as a neuroprotectant administered prior to surgery. The underlying antisense research into Alzheimer's has resulted in awards to Dr. Morley and his collaborators at St. Louis University (SLU) and in 2008 in a 5-year RO1 grant to Dr. Banks of SLU from the NIH. Edunn has recently been awarded a grant from the Alzheimer's Drug Discovery Foundation.

Representative Data

EDN-OL1 is a short nucleic acid. Specifically, EDN-OL1 is a phosphorothioate antisense oligonucleotide. Antisense oligonucleotides reduce biosynthesis of proteins with absolute specificity for their targets. Previously the antisense oligonucleotides were considered to have no utility as CNS drugs because they "could not cross the blood brain barrier into the brain." Drs. Banks, Morley, Kumar, Farr, and their colleagues have published a body of work to demonstrate that four different antisense oligonucleotides specifically reduce production of four different proteins in the brain with the predictable biochemical and behavioral consequences.

Figure 1

IV Treatment of EDN-O in Aged SAMP8 Mice

Mean Trials - Lower is Better

Edunn's AD drug is EDN-OL1 which is a specific antisense oligonucleotide that penetrates the blood - brain barrier and targets mRNA to reduce biosynthesis of amyloid precursor protein. The restoration of the cognitive function retention, which we would consider the ability to remember, or memory, (Figure 1, data generated by Drs. S. Farr, W.A. Banks, and J. Morley) has been demonstrated by behavioral testing of SAMP8 mice, an animal model of AD. As they age, SAMP8 mice lose the abilities to learn and remember. At age 12 months, SAMP8 mice have profound difficulties with learning and memory, but after three doses of EDN-OL1 perform as well in tests of learning and memory, as 4 month old mice, an age at which SAMP8 mice have no learning or memory problems. EDN-OL1 was manufactured by Agilent Technologies for Edunn, and when fully developed and approved for marketing will be the "drug in the bottle." These data were included in the presentation to NIH-RAID.

Earlier testing with EDN-OL1m (Murine sequence)

EDN-OL1m, the murine sequence, has restored cognitive function in three mouse models of AD: SAMP8 and transgenic Tg2576 models of AD, and Ts65Dn model of Down syndrome, a condition for which it is known that all patients come down with AD beginning at age forty. The connection between Down syndrome and AD is thought to be a consequence of the extra amyloid proteins arising from a third copy of the APP gene because DS patients have three rather than two copies of chromosome 21. Treatment with EDN-OL1m also has been demonstrated to end oxidative damage of proteins in the brain and to restore efflux of ABP that is reduced in AD.

In the SAMP8 mouse model of AD, ABP levels and cognitive dysfunction increase with age. EDN-OL1m was administered by intracerebroventricular (ICV) dosing - surgically put into the ventricle or cavity in the middle of the brain - and demonstrated to reduce levels of ABP compared to control dosing with a random sequence or "nonsense" oligonucleotide. ABP was reduced in the amygdala, the septum, and in the hippocampus - all regions of the brain know to be involved in Alzheimer's disease.

The ICV delivery needed to be improved upon for administration of EDN-OL1 to patients. The SLU investigators next demonstrated that EDN-OL1m administered by intravenous injection enters the brain and accumulates in the areas mentioned above that are involved in AD and have high levels of APP messenger RNA (mRNA) and ABP. The IV dosed EDN-OL1m reduced ABP, oxidative damage to proteins and lipids, restored to normal the otherwise reduced efflux of ABP, and most significantly, restored cognitive function. Aged (12 month) cognitively impaired SAMP8 mice had learning and memory restored to the levels measured in 4 month old unimpaired SAMP8 mice. The figure below represents the amount of practice (trials) these mice needed to learn and remember. The lower numbers show that learning and memory improved in treated mice.

Figure 2

IV Treatment of EDN-OL1m in Aged SAMP8 Mice

Mean Trials - Lower is Better

Development Status

Edunn has taken EDN-OL1 into preclinical development. The manufacturing process development for the pharmaceutical grade EDN-OL1 yields 97% purity. Animal studies have demonstrated that the compound enters the brain when administered via intravenous, subcutaneous, or intranasal dosing.

Intellectual Property

Edunn has an exclusive worldwide license from Saint Louis University for all intellectual property, including improvements, relating to CNS antisense applications. Patents protecting EDN-OL1 and EDN-OL202 are either issued or applications have been submitted. The current patent estate includes 1 issued US patent (6,310,048) and 3 PCT applications. Patent applications for EDN-OL1 could extend the period of exclusivity to year 2029.