=============================================================== == == == ----------- ALS INTEREST GROUP ----------- == == ALS Digest (#79, 10 January 1994) == == == == ----- amyotrophic lateral sclerosis (ALS) == == ----- motor neurone disease (MND) == == ----- Lou Gehrig's disease == == ----- == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. Currently there are == == 190+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == == == All interested people may "broadcast" messages to == == ALS Digest (not a peer reviewed journal, and not edited == == by an MD) subscribers by sending to: == == als@huey.met.fsu.edu == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. another citation from the literature on ALS 2 .. re: Cephalon, IGF-1, etc. 3 .. re: review of neurotrophic growth factors =============================================================== (1) ===== another citation from the literature on ALS ========== =============================================== Title : Molecular genetics in neurology Author : Martin J.B.; Source : 1993 34/6 (757-773) ANNED Annals of Neurology Abstract : There has been remarkable progress in the identification : of mutations in genes that cause inherited neurological : disorders. Abnormalities in the genes for Huntington : disease, neurofibromatosis types 1 and 2, one form of : familial amyotrophic lateral sclerosis, fragile X : syndrome, myotonic dystrophy, Kennedy syndrome, : Menkes disease, and several forms of retinitis pigmentosa : have been elucidated. Rare disorders of neuronal : migration such as Kallmann syndrome, Miller-Dieker : syndrome, and Norrie disease have been shown to be due : to specific gene defects. Several muscle disorders : characterized by abnormal membrane excitability have : been defined as mutations of the muscle sodium or : chloride channels. These advances provide opportunity : for accurate molecular diagnosis of at-risk individuals : and are the harbinger of new approaches to therapy of : these diseases. (2) ===== re: Cephalon, IGF-1, etc. ========== OTC 01/10 0811 ( BW)(CHIRON/CEPHALON)(CHIR)(CEPH) Chiron and ... Business Editors/Biotechnology Writers EMERYVILLE, CALIF. (JAN. 10) BUSINESS WIRE - Chiron Corporation (NASDAQ:CHIR) and Cephalon, Inc. (NASDAQ:CEPH) Monday announced that they have established a collaboration for the research, development and marketing of products for the treatment of neurological disorders. The collaboration will focus initially on the development of recombinant human insulin-like growth factor (IGF-1) for the treatment of amyotrophic lateral sclerosis (ALS) and a variety of peripheral neuropathies. IGF-1, under the tradename Myotrophin, is currently in clinical development for the treatment of ALS by Cephalon. The collaboration also will develop Chiron's human superoxide dismutase (hSOD), basic fibroblast growth factor (bFGF) and Cardioxane for neurological disorders. Under terms of the agreement, Chiron and Cephalon will share equally certain costs and profits over the life of the collaboration in North America and Western Europe. Chiron primarily will be responsible for selling products resulting from the collaboration in North America and Europe, and Cephalon will have the right to promote and sell these products directly to neurologists. In the remainder of the world, except Japan, Chiron will commercialize the products and will pay a royalty to Cephalon. Chiron will have the major responsibility for manufacturing IGF-1 and other compounds in the collaboration, however Cephalon will continue to manufacture IGF-1 for ongoing clinical trials and has the option to participate in manufacturing IGF-1 for commercial purposes. Clinical and marketing strategies and budgets will be established jointly, and Cephalon primarily responsible for conducting current clinical trials. As part of the agreement, Chiron will purchase 750,000 shares of common stock and warrants to purchase an equal number of shares from Cephalon for an aggregate purchase price of $15 million. "We are pleased to have Cephalon as a partner," said William J. Rutter, Ph.D., Chiron's chairman. "They have developed a strong research and development program in neurodegenerative diseases, and in particular have considerable experience with IGF-1. This complements our IGF-1 program and significantly expands the potential uses of IGF-1 for neurological indications. The collaboration also provides an effective vehicle for development of several of our other products for neurological indications. The combined knowledge and skills of the two companies establishes a strong competitive position in an attractive area." "This collaboration brings together two complementary biotechnology organizations with demonstrated capabilities in neuroscience research, drug development, manufacturing and marketing," said Frank Baldino, Jr., Ph.D., president and chief executive officer of Cephalon. "We welcome the opportunity to expand the potential neurological indications for IGF-1 and to develop new products with Chiron. We look forward to a productive and successful partnership." Background on Compounds for Collaboration IGF-1 is a naturally occurring hormone which among other potential activities mediates the recovery of peripheral nerves from injury. In preclinical studies, IGF-1 has been shown to promote the survival of sensory and motor neurons and enhance their regeneration when damaged. Cephalon currently is conducting Phase II/III clinical trials studying the use of IGF-1 (Myotrophin) to treat ALS (Lou Gehrig's disease) and expects to begin Phase II trials to study its use in treating certain neuropathies later this year. Chiron is conducting or planning trials studying the use of IGF-1 for treatment of tissue wasting, kidney function and a number of other degenerative and metabolic diseases. Superoxide dismutase (SOD) is an enzyme which may be useful in limiting oxidative damage resulting from reperfusion and head injury. Researchers recently have shown that mutations in the SOD gene may underlie the etiology of "familial," or inherited forms of ALS. Chiron previously conducted a Phase III clinical trial of SOD in kidney transplant surgeries following reperfusion. Chiron is analyzing the data from this trial for long-term kidney survival. Cardioxane is an antioxidant that is sold by Chiron in Europe, as an adjunct therapy to mitigate cardiac side effects in cancer patients undergoing treatment with doxorubicin, a commonly used chemotherapeutic agent. Fibroblast growth factor (bFGF) is one of several growth factors thought to play a role in the formation of blood vessels, muscle and connective tissue in wound healing. Chiron Corporation is a biotechnology company headquartered in Emeryville, California, near San Francisco. Chiron is building a healthcare business that addresses needs in several markets: diagnostics, including immunodiagnostics and new quantitative tests based on nucleic acid probe technology; vaccines, emphasizing adult and pediatric infectious diseases; therapeutics, with an emphasis on oncology, endocrinology and serious infectious and other diseases requiring critical care and opthalmology. Cephalon, Inc. is a leader in the discovery and development of products to treat neurological diseases and disorders. The company's principal focus is on neurodegerative diseases such as amyotrophic lateral sclerosis (Lou Gehrig's disease), peripheral neuropathy, Alzheimer's disease, head and spinal cord injury, and stroke. CONTACT: Chiron Corporation, Emeryville Larry Kurtz, 510/601-2476 Cephalon, Inc., West Chester Jason Rubin, 215/344-0200 Ext. 302 (3) ===== re: review of neurotrophic factors ========== AN 2190368 9312. TI NEUROTROPHIC FACTORS: CHANGING NEUROLOGY. SO Marketletter, 931220, December 20, 1993, ISSN NUMBER 0140-4288. YR 93. PU Marketletter (Publications) Ltd. AV Subscription: 440 British Pound Sterling per year as of 1/92. Published weekly. Contact Marketletter (Publications) Ltd., 54/55 Wilton Rd., London SW1V 1DE, UK. Phone (71) 828-7272. FAX (71) 828-0415. Over the last ten years, a shift has occurred within clinical neurology away from the standard notion that the brain is a static organ, incapable of repair. One of the foremost challengers to this outdated notion is Ira Black of the Robert Wood Johnson Medical School in the USA, who is heading a team concentrating on the idea of brain plasticity, the manner in which neuronal structure and function can change in response to stimuli, either from the genes or from changes in the molecular environment. Speaking at the recent American Society for Neuroscience annual meeting, Dr Black said that significant progress has been made in identifying some of the agents which give the central nervous system its plasticity. Most of the research has focused on the neurotrophic factors, a loose family of proteins known to be critical for the normal functioning of neurons. Neurotrophic factors have three primary functions, noted Dr Black: establishment of the nervous system during development; preservation and repair of neurons following damage; and promotion of growth and neuronal connections during the processes of learning and memory. Only a handful of neurotrophic factors have been identified to date, the foremost being nerve growth factor. NGF regulates the formation and maintenance of synaptic connections between peripheral neurons and their targets, and is considered necessary for the normal survival of sympathetic and sensory neurons. The factor is also implicated in learning and memory, since nerve activity seems to enhance its production and causes stronger connections among neurons. Genentech holds patents on NGF and is evaluating the drug in Phase II studies for the treatment of peripheral neuropathy, while other companies, including Synergen, Alkermes and Cytotherapeutics, are looking into its potential as an Alzheimer's disease treatment. The second neurotrophic factor to be discovered was brain-derived neurotrophic factor, by Hans Thoenen and colleagues at the Max Planck Institute in Munich, Germany, in 1987. BDNF is now known to be involved in development by stimulating attachment of nervous tissue to the developing musculature. The factor also seems to keep neurons alive, even after their long axons have been cut, can stimulate the partial survival of the two types of neurons which are central to the pathology of Parkinson's and Alzheimer's disease, and possesses neuroprotective as well as degenerative properties. Regeneron has acquired rights to BDNF from the Max Planck Institute, and is primarily developing the drug as a treatment for amyotrophic lateral sclerosis, in collaboration with Amgen. ALS is likely to be one of the first neurodegenerative diseases to benefit from therapy with neurotrophic factors because delivery across the blood-brain barrier is not required. The discovery of BDNF was closely followed by the finding of another protein, ciliary neurotrophic factor, by Silvio Varton at the University of California at San Diego, USA. CNTF contributes to the survival, function and regeneration of neurons in the periphery, that convey sensation and control the function of muscles and organs. Synergen and Regeneron are developing CNTF for therapeutic purposes, initially for amyotrophic lateral sclerosis and peripheral neuropathy. The two companies are in the midst of a legal wrangle over patent rights. The most recent discovery, glial cell-line derived neurotrophic factor, was identified this year by Frank Collins at Synergen in Boulder, Colorado, USA. It is named after the glial cells which comprise 90% of the brain's cells, and are now known to be primary producers of neurotrophic factors and an integral part of the homeostasis and communication system in the brain. Researchers at Synergen have already shown that GDNF speeds up maturation of embryonic neurons and enhances their survival and ability to communicate with neighbouring cells. Interestingly, GDNF appears selectively to promote survival of dopaminergic neurons, those which typically degenerate in Parkinson's disease. Other neurotrophic factors which have been discovered include neurotrophin-3 and neurotrophin-4, and insulin-like growth factor, which Cephalon is assessing as a treatment for ALS. As intimated earlier, the major drawback in neurotrophic factor therapy is the fact that these large molecules currently need invasive routes of administration if they are to be used to treat CNS disorders. Companies such as Cytotherapeutics and Alkermes are attempting to develop novel formulations to facilitate this, but an important advance in the future of neurotrophic therapy will be the development of small, low molecular weight mimics of the neurotrophic factors. Researchers at the University of Kentucky, USA, have reported that they are a step closer to developing small-molecule mimics of neurotrophic factors, following the discovery that compounds isolated from bacteria can activate receptors for neurotrophic factors found on neurons. Mark Mattson and colleagues have conducted their research on nerve cell culture and animal models of ischemic stroke. A number of neurotrophic factors, including NGF, fibroblast growth factor and IGF, have been shown to have neuroprotective properties in ischemic conditions similar to those encountered in stroke. However, rather than concentrating on means of getting these factors across the blood-brain barrier, Dr Mattson's team took a different approach. Over the last four years they have identified various mechanisms by which neuroprotective factors spare the brain cells from ischemic injury. It was found that they prevent the accumulation of calcium and free radical levels in neurons which otherwise occurred as a result of ischemia. The next stage of the research involved finding small molecules which interact with the receptors for neurotrophic factors on neurons and stimulate relevant signal transduction pathways within the cell. Dr Mattson's team has identified certain alkaloid compounds, including staurosporin, K-252a and K -252b, which can achieve this and are effective in preventing neuronal death in animal models of stroke. They are now developing parenteral and oral candidates, ideally which interact selectively with a single neurotrophic factor receptor, for human clinical use. == end of als 79 ==