=============================================================== == == == ----------- ALS INTEREST GROUP ----------- == == ALS Digest (#82, 14 February 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 == == 200+ 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 subscribers by sending to: == == als@huey.met.fsu.edu == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. ALS & Pain 2 .. programmed cell death 3 .. re: SOD1 4 .. re: SOD1 (more) 5 .. Occupational & Environmental Medicine (LISTSERV) 6 .. ALS & neurotoxins (sample citations) (1) ===== ALS & Pain ========== >From : kreamer@mcis.messiah.edu Date : Mon, 14 Feb 94 16:45:00 +0000 Subject: ALS and Pain This is a request for information for a colleague whose sister has ALS. Her sister seems to be experiencing a considerable amount of pain -- specifically, joint pain in spite of large amounts of analgesic and sedatives. Namely, she receives morphine, halcion, and tylenol #3, but continues to be unable to rest comfortably. Is this a common problem? What is its cause--contractures, degenerative changes associated with the disease, or something else? None of the literature addresses this problem, and no one seems to be able to help. Is anyone else out there familiar with this problem, and how are you handling it? Carolyn L. Kreamer kreamer@mcis.messiah.edu (2) ===== programmed cell death ========== LA JOLLA, Calif., Feb. 3 /PRNewswire/ -- IDUN Pharmaceuticals Inc. today announced that it has entered into a licensing agreement with the Massachusetts Institute of Technology for a broad portfolio of programmed cell death (apoptosis) technologies based on the original discoveries made by M.I.T.'s H. Robert Horvitz, Ph.D. and Herman Steller, Ph.D. The license covers the genes ced-3, ced-9, rpr and their human homologues as well as assay systems to screen cells for cell death and to screen compounds which promote or prevent cell death, according to Lawrence C. Fritz, Ph.D., IDUN's vice president of research and development. The concept that cells actively participate in their own death opens up an entirely new spectrum of approaches for treating hyperproliferative diseases such as cancer as well as neurodegenerative diseases and inflammation, Fritz said. Our aim is to develop therapeutics that exploit these newly discovered cell death pathways. Through his work at M.I.T. on the development of the roundworm Caenorhabditis elegans, Horvitz discovered the ced-3 gene (cell death gene 3) and characterized its fundamental role in apoptosis. In a paper in the Nov. 19, 1993 issue of Cell, Horvitz and his research team showed that the ced-3 gene produces an enzyme which causes cell death. The roundworm ced-3 protein is similar to a superfamily of proteases related to the human ICE protein, suggesting a similar mechanism for programmed cell death may exist in humans. Horvitz also discovered the ced-9 gene which appears to control the ced-3 gene by negative regulation and prevents cells from dying. The human homologue of ced-9 is the proto- oncogene Bcl-2 Programmed cell death is an essential process in maintaining the balance between the growth of new cells and the elimination of old cells. In order to function properly, the body must tightly regulate the number of cells in each of its organs and tissues. When this control is lost, the result can be either an abnormal increase in cell number, as in cancer, or an abnormal loss of cells, such as in degenerative diseases or as a result of tissue damage caused by heart attack, injury or inflammation. Historically, research has focused primarily on the mechanisms of cell proliferation. Recently, however, scientists have discovered that virtually all cells can specifically regulate their rate of death through the action of specific genes that control the cell death process. IDUN is focusing its efforts on the discovery and development of drugs that act by modulating these gene products and on identifying new drug discovery targets within the cell death pathway. Horvitz, professor of Biology at M.I.T. and chairman of IDUN's scientific advisory board, is a recognized leader in the identification and characterization of cell death genes. His work includes the recent discovery of the gene causing familial amyotrophic lateral sclerosis, the neurogenerative disorder known as Lou Gehrig's disease. Steller, associate professor of Neurobiology at M.I.T., is a leader in the identification of the genes responsible for the development of Drosophila. He recently discovered the gene reaper that enables cell death in the developing fly. IDUN Pharmaceuticals is a privately held company focused on pharmaceutical manipulation of the process of cell death. Based on its proprietary technologies, the company intends to develop small molecule therapeutics to treat a variety of intractable human diseases, such as cancer, inflammation and degenerative diseases. The company was founded in 1993 by Fritz and Avalon Ventures' Lawrence A. Bock and Joel F. Martin. Bock, general partner at Avalon Ventures, is the acting chief executive officer of IDUN Pharmaceuticals Inc. Fritz and Avalon were also co-founders of Athena Neurosciences. In addition, Avalon Ventures has been responsible for the start-up and financing of numerous biotechnology companies including ARIAD, GenPharm International, NeoRx, Neurocrine Biosciences, Pharmacopeia, Onyx Pharmaceuticals, Sequana Therapeutics and Vertex Pharmaceuticals. CONTACT: Joel F. Martin, Ph.D., VP-Finance and Business Development : IDUN Pharmaceuticals, 619-454-3803, ext. 39; or : Linda Seaton, Keatinge/Seaton Communications, 619-625-2100 (3) ===== re: SOD1 ========== Monday February 14, 1994 SO THEY'VE FOUND THE GENE FOR YOUR DISEASE. WHAT NOW? By MALCOLM RITTER AP Science Writer NEW YORK (AP) -- The headline -- ``Scientists Discover Gene That Causes Disease'' -- seems like the payoff in a pulp novel, when the detectives finally track down a killer and flush him from his lair. But while the denouement of a murder mystery briskly ties up all the loose ends, genetic research is another thing entirely. The public may expect that a discovery means that a new test, treatment or cure is imminent -- and sometimes, it is. But sometimes the trail is long and challenging. Nothing illustrates that better than what researchers face in exploiting three major gene discoveries announced in 1993: those involving colon cancer, Lou Gehrig's disease and Huntington's disease.
As with the colon cancer gene, the discovery of a gene causing some cases of Lou Gehrig's disease immediately suggested a possible direction for a payoff. But the prospects for success here are less clear. Lou Gehrig's disease is formally called amyotrophic lateral sclerosis, or ALS. It causes progressive paralysis by destroying muscle-controlling nerves in the brain and spinal cord. It usually begins in middle adulthood, generally causing total paralysis and death within two to five years. Only about 10 percent of ALS is caused by faulty genes, and the newly identified gene is responsible for only about a quarter of this inherited ALS. But researchers hope leads from the gene will apply to the disease in general. And they got quite a lead. The gene was a well-known one that oversees production of a substance called superoxide dismutase 1, or SOD1, which in turn helps the body destroy toxic substances called free radicals. So if defects in the gene reduce the effectiveness of SOD1, at least some ALS might be caused by buildups of free radicals. That in turn meant that readily available ``antioxidant'' substances that combat free radicals, including some vitamins, might be useful against ALS. Scientists have confirmed that a defective gene leads to reduced SOD1 effectiveness, said Dr. Robert Brown of Massachusetts General Hospital in Boston. There is also some preliminary evidence that free radical buildup may play a role in noninherited ALS. The noninherited form might result from defects in multiple genes that affect the handling of free radicals, in combination with some sort of environmental trigger, said Dr. Teepu Siddique of Northwestern University. Some people with the defective SOD1 gene remain free of ALS until very late in life, Siddique said. If scientists can identify why, they might find a way to delay ALS so long that it doesn't appear during a person's lifetime, he said. Meanwhile, scientists are planning to test whether people with inherited ALS can be helped by infusions of SOD1 into their spinal fluid.
(4) ===== re: SOD1 (more) ========== Please note that the previous note mentioned that "scientists are planning to test whether people with inheritad ALS can be helped by infusions of SOD1 into their spinal fluid". The following is from the newsletter of the Center for Neurologic Study (CNS). Article title: ALS GENE DISCOVERY "With the announcement of the gene discovery researchers have begun to consider their treatment options. As a first step in trying to provide replacement enzyme therapy for patients with familial ALS, CNS has undertaken the treatment of a patient with superoxide dismutase. Unfortunately, treatment is complicated by the fact that large proteins do not reach the brain due to the existence of a "blood- brain barrier". One way to get around this is to inject SOD directly into the spinal fluid. Before undertaking this in a human, arrangements were made with researchers at the National Institute of Health to conduct studies in monkeys. Intraventricular and intraspinal injections of SOD into monkeys appeared to be well tolerated. Based on this, approval was given to CNS to proceed with human studies. These are the first ever undertaken in ALS patients. Pharmacokinetic data indicate that it is possible to achieve high levels of SOD in the spinal fluid. It is hoped therapy will arrest the disease process." There was no by-line to the article but no doubt more information can be provided by: Richard A. Smith, MD Director Center for Neurologic Study (CNS) 11211 Sorrento Valley Road, Suite H San Diego CA 92121 TEL 619-455-5463 FAX 619-455-1713 (5) ===== Occupational & Environmental Medicine (LISTSERV) ========== Date : Thu, 3 Feb 1994 13:26:20 CST Sender : NEW-LIST - New List Announcements >From : GREEN011@mc.duke.edu Subject: NEW: Occ-Env-Med-L - Occupational and Environmental Medicine -------------------------------------------------------------------- Occ-Env-Med-L on mailserv@mc.duke.edu Occupational and Environmental Medicine Occupational & Environmental medicine represents a growing clinical and public health discipline, seeking to evaluate and prevent the diseases and health effects that may be related to exposures at work and from other environments (eg pollution). The Occ-Env-Med-L Mail-list provides a forum for announcements, dissemination of text files and academic discussion. The forum is designed to allow presentation of clinical vignettes, synopses of new regulatory issues and reports of interesting items from publications elsewhere (both the medical and the non-medical journals). The Association of Occupational & Environmental Clinics represents the first nucleus of members for the list, and will use the list for announcements. AOEC members are either: A) interested clinics with approved credentials documenting expertise in Occupational & Environmental Medicine B) individuals interested in sharing this topic, but who have no requirement to show advanced training or expertise. Professional affiliations of the Mail-list subscribers will include: Occupational Physicians and Nurses Industrial Hygienists Government Public Health officials University investigators and regulators in Occupat & Environ Med diseases I imagine that the topics will include: - Case Presentations, ending with "what do I do next?" - Ethical concerns - Requests for technical expertise, usually free and off-the-cuff. - Requests for collaborators, either research or business. - Announcements of hot topics, including regulatory issues, case reports with effect on usual practice, news events. - Job postings and requests for offers. - You name it... This maillist is currently unmoderated. That means that anything sent to the list is BROADCAST to all subscribers (a pain if the msg is secret or even just trivial). Responses to messages CAN be selectively addressed (ie, to the individual who posted the message or to just a few individuals) and this is suggested for any message that the group as whole would find uninteresting (especially replies). In the future, we MAY limit posting to the maillist if the messages get too numerous, too inflammatory or just annoying, but for now it's open to all. If we decide to limit the volume, it will be called a "moderated" where a sysop (me, I guess) acts to approve information for posting, to reduce the volume of undesirable stuff that everybody else gets. How to Subscribe to Occ-Env-Med-L To place your name on the mail list, send a special message to the internet address mailserv@mc.duke.edu include just a single line message that says: SUBSCRIBE Occ-Env-Med-L "FirstName LastName" (you'll fill in the blanks, of course!) eg: SUBSCRIBE Occ-Env-Med-L "Gary Greenberg, MD MPH" Please put in your full name in quotes as the example shows. An optional parameter, the address to subscribe, may be specified with this commands. SUBSCRIBE Occ-Env-Med-L "Gary Greenberg" This would allow you to subscribe someone else to the list, or to use a second or different address than the one from which you are presently posting the subscription request. The mail list will otherwise use your return electronic mail address as the maillist subscription address. I expect that once the list is established, we'll also be able to accumulate a database of who's on the list (including an e-mail list), what topics interest us and what discipline we belong to. Owner: Gary Greenberg, MD GREEN011@mc.duke.edu (6) ===== re: ALS & neurotoxins (sample citations) ========== ========================================================== Title : Hypotheses to explain the association between vigorous : physical activity and amyotrophic lateral sclerosis. Author : Longstreth WT; Nelson LM; Koepsell TD; van Belle G Source : Medical Hypotheses 1991 Feb;34(2):144-8 ========================================================== Title : Slow non-NMDA receptor mediated neurotoxicity and : amyotrophic lateral sclerosis. Author : Weiss JH;Choi DW Source : Advances in Neurology 1991;56( ):311-8 ========================================================== Title : beta-Methylamino-L-alanine (BMAA) and amyotrophic : lateral sclerosis-parkinsonism dementia of the western : Pacific. Author : Duncan MW Source : Annals of the New York Academy of Sciences : 1992 May 11;648( ):161-8 ========================================================== Title : Amyotrophic lateral sclerosis: fasting plasma levels of : cysteine and inorganic sulfate are normal, as are brain : contents of cysteine. Author : Perry TL;Krieger C;Hansen S;Tabatabaei A Source : Neurology 1991 Apr;41(4):487-90 ========================================================== Title : Guam ALS/parkinsonism-dementia: a long-latency neurotoxic : disorder caused by "slow toxin(s)" in food? Author : Spencer PS Source : Canadian Journal of Neurological Sciences : 1987 Aug;14(3 Suppl):347-57 ========================================================== Title : 2-Amino-3-(methylamino)-propanoic acid (BMAA) in cycad : flour: an unlikely cause of amyotrophic lateral : sclerosis and parkinsonism-dementia of Guam. Author : Duncan MW;Steele JC;Kopin IJ;Markey SP Source : Neurology 1990 May;40(5):767-72 ============================================================= Title : Guam amyotrophic lateral sclerosis-parkinsonism-dementia : linked to a plant excitant neurotoxin. Author : Spencer PS; Nunn PB; Hugon J; Ludolph AC; Ross SM; : Roy DN; Robertson RC Source : Science 1987 Jul 31;237(4814):517-22 ========================================================== Title : Neurotoxins and degeneration in the central nervous system. Author : Calne DB Source : Neurotoxicology and Teratology 1991 Fall;12(3):335-9 ========================================================== Title : The neuroexcitotoxic amino acids glutamate and aspartate : are altered in the spinal cord and brain in amyotrophic : lateral sclerosis. Author : Plaitakis A; Constantakakis E; Smith J Source : Annals of Neurology 1988 Sep;24(3):446-9 =========================================================== Title : Motor unit function during evolution of proximal axonal : swellings. Author : Delio DA; Fiori MG; Lowndes HE Source : Journal of the Neurological Sciences 1992 May;109(1):30-40 =========================================================== Title : Role of the cycad neurotoxin BMAA in the amyotrophic : lateral sclerosis-parkinsonism dementia complex of the : western Pacific. Author : Duncan MW Source : Advances in Neurology 1991;56( ):301-10 =========================================================== Title : Amyotrophic lateral sclerosis: what makes the direct : corticospinal tract so vulnerable [editorial] Author : Kaji R; Kimura J Source : Muscle and Nerve 1993 Aug;16(8):872-4 =========================================================== Title : Slow toxins, biologic markers, and long-latency : neurodegenerative disease in the western Pacific region. Author : Spencer PS; Kisby GE; Ludolph AC Source : Neurology : 1991 May;41(5 Suppl 2):62-6; discussion 66-8 =========================================================== Title : Specific antagonism of excitotoxic action of 'uncommon' : amino acids assayed in organotypic mouse cortical cultures. Author : Ross SM; Seelig M; Spencer PS Source : Brain Research 1987 Nov 3;425(1):120-7 =========================================================== Title : Content of the neurotoxins cycasin (methylazoxymethanol : beta-D-glucoside) and BMAA (beta-N-methylamino-L-alanine) : in cycad flour prepared by Guam Chamorros. Author : Kisby GE; Ellison M; Spencer PS Source : Neurology 1992 Jul;42(7):1336-40 =========================================================== Title : Excitatory amino acid receptors in human spinal cord. : Evaluation in amyotrophic lateral sclerosis patients. Author : Allaoua H; Chaudieu I; Boksa P; Perry TL; Krieger C; : Quirion R Source : Annals of the New York Academy of Sciences : 1992 May 11;648( ):260-2 =========================================================== Title : Long-latency neurodegenerative disease in the western : Pacific. Author : Spencer PS; Kisby GE; Ludolph AC Source : Geriatrics 1991 Aug;46 Suppl 1( ):37-42 =========================================================== Title : Beta-N-methylamino-L-alanine. Chronic oral administration : is not neurotoxic to mice. Author : Perry TL; Bergeron C; Biro AJ; Hansen S Source : Journal of the Neurological Sciences : 1989 Dec;94(1-3):173-80 =========================================================== Title : Cycads and sago [letter] Author : Gilks CF Source : Lancet 1988 Jan 23;1(8578):181-2 =========================================================== Title : Are human neurodegenerative disorders linked to : environmental chemicals with excitotoxic properties? Author : Spencer PS; Ludolph AC; Kisby GE Source : Annals of the New York Academy of Sciences : 1992 May 11;648( ):154-60 Abstract : At the present time, it seems unlikely that progressive : neurodegenerative diseases, such as ALS, Parkinson's : disease, and dementia of the Alzheimer type, are : triggered by environmental agents with excitotoxic : potential. These include excitotoxic agents that behave : as glutamate agonists or disrupt energy metabolism: : both types elicit permanent but self-limiting neuronal : diseases with patterns of neuronal deficit that reflect : selective chemical exposure (MPP+ and parkinsonism), : differential susceptibility to energy dysmetabolism : (NPA and dystonia), or the distribution of glutamate- : receptors (domoic acid and memory loss). If environmental : agents play an etiologic role in progressive : neurodegenerative diseases, they are likely to target : a critical, irreplaceable neuronal molecule that is : required to maintain long-term neuronal integrity. =========================================================== == end of als 82 ==