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ArmaGen ProductsAGT-3--An intravenous siRNA delivery system AGT-120--A neuroprotection drug for stroke AGT-140--A second neuroprotective drug for stroke AGT-160--An anti-amyloid therapeutic for Alzheimer's disease AGT-181--A lysosomal enzyme replacement therapy for the brain AGT-185--A CNS-acting chemical nerve gas antidote AGT-190--A neuroprotection drug for stroke or Parkinson's disease AGT-2000--A non-viral gene therapy of brain cancer An avidin antibody fusion protein for intravenous RNAi and the in vivo delivery of short interfering RNA (siRNA) AGT-3 is a genetically engineered fusion protein of avidin and a monoclonal antibody to a human cell membrane receptor, which binds mono-biotinylated siRNA with high affinity to enable intravenous RNA interference. The avidin-biotin bond is highly stable in vivo, and the siRNA knocks down target mRNAs while still bound to avidin. Avidin is fused to a genetically engineered receptor specific monoclonal antibody (MAb), which is endocytosed by virtually all human cells, including the cells comprising the blood-brain barrier (BBB). ArmaGen's siRNA delivery system is encompassed within the broad claims of issued U.S. patent 6,287,792, which covers the use of avidin-biotin technology in drug delivery. A neuroprotection drug for stroke that crosses the blood-brain barrier and is active in brain following delayed intravenous administration
A second neuroprotection drug for stroke that crosses the blood-brain barrier and is active in brain following delayed intravenous administration AGT-140 is a second neuroprotective drug for stroke. Like AGT-120, AGT-140 is a genetically engineered recombinant fusion protein that is part molecular Trojan horse (MTH), and part neurotrophin. The MTH part of the drug binds a specific receptor on the human blood-brain barrier (BBB) to trigger receptor-mediated transport across the BBB and into brain from blood. The neurotrophin part of AGT-140 binds a specific receptor in brain that induces neuroprotection in acute stroke. AGT-140 acts at a different neurotrophin receptor than that targeted by AGT-120 (see above), and AGT-120 and AGT-140 effects in stroke will be additive, as the 2 neurotrophins induce neuroprotection in different regions of the brain. The Company intends to develop both AGT-120 and AGT-140 in parallel as part of a strategy for multiple neuroprotection therapy in acute stroke. These 2 drugs will not compete for the same market, but rather will "grow" the market for the other. An anti-amyloid drug that crosses the blood-brain barrier for reducing the brain amyloid burden of Alzheimer's disease AGT-160 is a genetically engineered large molecule anti-amyloid therapeutic for Alzheimers disease (AD). AGT-160 is a fusion protein formed by 2 different proteins. One part of the molecule inhibits the formation of beta-amyloid plaque, which causes the dementia of AD. The other part of the molecule is a molecular Trojan horse that crosses the human blood-brain barrier via a specific receptor-mediated transport system. The present market for anti-amyloid drugs such as AGT-160 is >12 million in the U.S. alone, and includes the 4 million people suffering from AD as well as the 8 million people with mild cognitive impairment (MCI). Because the brain amyloid deposits up to 20 years before the onset of symptoms, the market for AGT-160 is even larger than the 12 million people with AD or MCI. The number of people with AD or MCI will increase to 18 million in the U.S. by 2020. it is important that anti-amyloid neurotherapeutics (that cross the blood-brain barrier) be started years before the onset of the clinical signs of AD. The delay in onset of the symptoms of AD by just 5 years reduces U.S. health care costs by $50 billion per year. The market for anti-amyloid drugs such as AGT-160 may extend beyond AD to all individuals that begin accumulating beta-amyloid in their brain. It is essential that non-invasive imaging technology be developed so that people who begin depositing amyloid in brain (years before the onset of symptoms of AD) can be identified. New neurodiagnostic radiopharmaceuticals, such as AGT-100, that enable the early detection of brain beta-amyloid accumulation will grow the markets for anti-amyloid drugs such as AGT-160. AGT-160 is also a potential brain amyloid imaging agent, and could be the first dual purpose new chemical entity that can be used as either a neurodiagnostic or a neurotherapeutic for AD. A lysosomal enzyme replacement therapy for the brain AGT-181 is a new form of enzyme replacement therapy that is specifically indicated for the treatment of the brain for a lysosomal storage disorder. AGT-181 is a genetically engineered fusion protein. One part of the molecule is a lysosomal enzyme that is missing in a lysosomal storage disorder that affects the brain. The other part of the molecule is a molecular Trojan horse that crosses the human blood-brain barrier via a specific receptor-mediated transport system. The bi-functional AGT-181 molecule is a novel biopharmaceutical that binds a specific human BBB receptor at the "head" of the molecule, and contains a lysosomal enzyme at the "tail" of the molecule. This lysosomal enzyme is missing in the brain, and other organs, of patients born with a specific lysosomal storage disorder. There are over 40 Lysosomal Storage Disorders and about 75% of these severely affect the central nervous system (CNS). Conventional Enzyme Replacement Therapy (ERT) does not treat the brain in patients with Lysosomal Storage Disorders, because the enzyme therapeutic does not cross the BBB. Thus, the enzyme cannot penetrate into the brain from the blood. Enzyme replacement therapy of the CNS is a goal of ERT, and ArmaGen's solution to the BBB problem may enable enzyme replacement therapy of the brain with a conventional intravenous infusion, providing the missing enzyme is re-formulated to enable penetration of the BBB in humans. A CNS-acting chemical nerve gas antidote Chemical nerve gas agents cause morbidity and mortality via action within the central nervous system (CNS). Therefore, it is important that antidotes against chemical nerve gas agents are enabled to cross the human blood-brain barrier (BBB). AGT-185 is a fusion protein of a human BBB molecular Trojan horse and a human serum enzyme with high hydrolytic activity against chemical nerve gas agents. AGT-185 is a bi-functional molecule that both crosses the human BBB and hydrolyzes organophosphates, and is the first organophosphatase enzyme ever engineered to specficially cross the human BBB. The AGT-185 drug development program is funded by the NIH Counter Measures Against Chemical Threats (CounterACT) Research Network. A neuroprotection drug for stroke or Parkinson's disease AGT-190 is a genetically engineered fusion protein that is comprised of a human neurotrophin that causes neuroprotection in the brain, and is indicated acutely for the treatment of stroke, and chronically for the treatment of Parkinson's disease (PD). The neurotrophin forming AGT-190 is a large molecule, which does not cross the blood-brain barrier (BBB), and cannot enter the brain following peripheral administration. The neurotrophin is fused to another protein that undergoes receptor-mediated transport across the human BBB; the second protein acts as a molecular Trojan horse to ferry the therapeutic neurotrophin across the BBB into brain from blood. The AGT-190 fusion protein is a bi-functional molecule: it both attaches to a receptor on the human BBB, to cause transport into the brain from blood, and it attaches to a specific neurotrophin receptor on brain cells to protect the cells from cellular damage. AGT-190 is the first neurotrophin treatment specifically engineered to cross the BBB for the long-term treatment of PD. A non-viral, intravenous gene therapy for either primary or metastatic brain cancer AGT-2000 is non-viral gene therapy of brain cancer that is active following weekly intravenous injections. ArmaGen's proprietary molecular Trojan horses carry the plasmid DNA across the blood-brain barrier of brain cancer and across the brain cancer cell membrane to the nucleus of the cancer cell deep within the brain. The gene medicine can either "knock out" oncogenic genes with antisense gene therapy or "knock in" mutated tumor suppressor genes with replacement gene therapy. The potential market for AGT-2000 is large. There are are approximately 150,000 cases of metastatic brain cancer and 15,000 cases of primary brain cancer in the U.S. each year, and over 70% of these cancers are dependent on the same oncogene, which is knocked out by AGT-2000. ArmaGen's approach to gene therapy of brain cancer, and to gene therapy in general, is non-viral and non-invasive. No viruses are used in the formulation, and ArmaGen gene therapies are administered non-invasively with only weekly intravenous administrations. The ability of AGT-2000 to knock out an oncogene, the human epidermal growth factor (EGF) receptor, in human brain cancer cells is shown in the 2 movies below. In the movie on the left, a wave of intracellular calcium transport is seen following the addition of EGF to the brain cancer cells. In the movie on the right, the same brain cancer cells are stimulated with EGF, but after 24 hours of treatment with AGT-2000. The gene therapy nearly completely abolishes the expression of the EGF receptor in the brain cancer cells. This is accomplished without viruses and with a formulation that is stable in the bloodstream, and able to target distant sites in the body following an intravenous administration of the gene therapy.
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