Date: Thu, 11 May 95 01:48:35 -0400 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD191 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#191, 09 May 1995) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ------ maladie de Charcot == == == == 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. The ALS Digest is == == published (approximately) weekly. Currently there are == == 690+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. shareholder meeting statement 2 .. RE: Multifocal Motor Neuropathy 3 .. New Book on MND 4 .. MDA Research Report #56 (1) ===== shareholder meeting statement ========== Date : Wed, 10 May 1995 22:02:56 EDT >From : UKRY13A@prodigy.com (MR JOSEPH L SNYDER) Subject: Re: shareholder mtg. statement BELOW IS A STATEMENT I HAD DON ALTIER READ FOR ME AT THE MAY 9TH AMGEN SHAREHOLDER MEETING. AMGEN HAS NOW DECIDED TO TEST GDNF ON ALS IN HUMANS THIS YEAR. THIS IS A BIG WIN FOR ALL OF US WHO HAVE BEEN PUSHING AMGEN FOR SEVERAL MONTHS. STILL NEED TO COVINCE THEM ON COMBO TEST(CNTF/BDNF) AND NUKING OF UNETHICAL PLACEBOS. JOE SNYDER Mr. Binder-My name is Joe Snyder. Unfortunately I was unable to attend this meeting today because I have a bad case of ALS. My friend and fellow ALS victim Don Altier, who can still talk will read my statement and questions. I am an Amgen shareholder, a faithful guinea pig in your BDNF ALS trial and an executive at GE with extensive experience in mergers, acquisitions,strategy and industrial restructuring. I must start by commending you on a very astute acquisition of Synergen. However I am puzzled by your strategy. You stated in your annual report that you expected to begin human trials of Synergen drug GDNF on Parkinsons disease this year. This is good news for shareholders and those suffering from Parkinsons. My first question is, when do GDNF human trials on ALS begin? As you know several published independent animal tests demonstrated that GDNF has great potential as a treatment for ALS. Why would you not want to optimize this drug and also pursue what many on Wall Street estimate as at least a several hundred million dollar U.S. ALS market and a worldwide market between $ 500 million to a billion? Certainly there are synergistic COST and TIME savings by utilizing GDNF to pursue both diseases (for instance animal safety and toxicity tests would only need to be performed once etc.). My next question concerns your apparent unwillingness to supply respected ALS researcher Dr. Mitsumoto of the Cleveland Clinic with CNTF/BDNF for a ALS combo trial. Certainly you are aware of Dr. Mitsumoto's published animal study showing the synergistic effects of CNTF/BDNF combination. WELL OVER A YEAR AND A HALF AGO it was shown that this combination STOPPED the progression of Motor Neuron Disease in animals. Dr. Mitsumoto has been waiting since DECEMBER for an answer from Amgen. When will you stop delaying this small trial which for a relatively small expense could have a huge payback? Now I would like to talk to you about leadership. You are very fortunate to be the leader of a great company such as Amgen at this point in history. The winds of change are blowing thru the bloated halls of the FDA. As the leader of Amgen you have an enormous opportunity to change some stodgy FDA driven practices that are not only unethical to those suffering from terminal illnesses but will continue to cost shareholders millions of dollars. Drug development and trial cycle time must and can be reduced. From start to finish drug development cycle time logically can be divided into two parts, scientific and administrative. Scientific is the total of lab. work, animal and human testing. In this scientific area Amgen is using the best equipment and pressing to reduce time with innovation. On the ADMINISTRATIVE side Amgen is tediously slow and mired in a 1950's style paper-shuffle with the FDA dominating the process. This FDA leadership ignores modern administrative technology thus avoiding the massive cycle time reductions which have been a part of life in all other American industries. Please hire a trained industrial process mapper to examine your drug development cycles and with your leadership cut months and years out of the drug development process. The technology is now available to conduct REAL TIME human drug trials, if you fail to take advantage of it, then other innovative companies will leaving Amgen behind. IT IS TIME TO CHANGE THE GAME, SAVE YOUR SHAREHOLDERS HUNDREDS OF MILLIONS OF DOLLARS AND SAVE SOME LIVES. THE POLITICAL CLIMATE IS RIPE FOR CHANGE IN WASHINGTON, BE A LEADER NOT A FOLLOWER. Last but not least the unethical and costly practice of using placebos for ALS human trials must be stopped. ALS is over 100 years old and there are literally mountains of data at the FDA and with recent CNTF trials by Synergen and BDNF trials by Amgen, it is now very easy for you to construct an accurate mathematical control group. Do not sacrifice any more human beings with ALS on this placebo altar of lazy science and waste trial money in the process. Again it is time to lead, not follow the FDA. THANKS FOR YOUR TIME. JOE SNYDER, 11503 ARBOR COURT, LOUISVILLE KY. 40223 Statement read by Don Altier, a 35 year father of twin two year old sons from San Jose, CA. Don was diagnosed with ALS - Lou Gehrig's Disease on Oct. 13,1992 - the day after he and his wife Carrie found out that she was pregnant with twins. (2) ===== RE: Multifocal Motor Neuropathy ========== Date : Mon, 08 May 95 23:04:01 -0400 >From : "Dr. Kenneth Fischbeck" Subject: RE: Multifocal Motor Neuropathy To : boonegolf@aol.com.in Cc : bro@huey.fsu.edu.in Multifocal motor neuropathy is an inflammatory condition of the motor nerves that has been defined relatively recently. It causes muscle weakness and atrophy (lower motor neuron signs) as in ALS, but without spasticity and increased reflexes (upper motor neuron signs). It is diagnosed primarily by electromyography and nerve conduction study. The diagnosis is important to make, because patients with the disorder can benefit from treatment, e.g., with intravenous immunoglobulin. If you feel multifocal motor neuropathy is a possibility, it is worth asking your neurologist about it. K. Fischbeck, M.D. Neurology Dept., Univ. Pennsylvania (3) ===== New book on MND ========== Date : Wed, 10 May 1995 12:20:25 +0000 >From : James.Lowe@nottingham.ac.uk (Jim Lowe) Subject: New book on MND Springer Verlag have just produced a new book on ALS. Motor Neuron Disease: Biology and Management. PN Leigh & M. Swash (Eds) 86 Figs 469 pages Hardcover DM 218, sFr 205 This is an excellent multi-author book aimed at professional health workers who have an interest in ALS. The contents cover the whole spectrum of ALS with chapters on clinical features, epidemiology, familial disease, pathology, neurochemistry, theories of causation, physiology, biology of motor systems, clinical pharmacology, management, clinical trials and new therapeutic approaches. The standard is very high with incorporation of latest references. Some of the chapters are unique, with data not easily available from other sources. Illustrations are in black/white but are all of high quality. There are nice overviews of aspects of molecular biology and genetics. While the book is aimed at the professional medical market, it is so clearly written that I can recommend it as a very good source book for up-to-date information for anyone else. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ >From Dr. Jim Lowe Reader and Consultant in Neuropathology Email: James.Lowe@nott.ac.uk Dept. Pathology University of Nottingham Medical School Clifton Boulevard Nottingham Tel (0115) 9709269 NG7 2UH fax (0115) 9709759 UK ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ===== = How to order: = For USA/Canada/Mexico: orders@springer-ny.com = For rest of world: orders@springer.de = A contact person: ccraft@springer-ny.com = Related addresses: = GopherMaster@gopher.springer-ny.com = WebMaster@www.springer-ny.com = http://www.springer-ny.com = ListMaster@lists.springer-ny.com = listproc@lists.springer-ny.com Subject: email Message: help = FtpMaster@ftp.springer-ny.com = = WebMaster@vax.ntp.springer.de = Springer-Verlag = Tiergartenstr. 17 = D-69121 Heidelberg = GERMANY = TEL x-49-6221-487-488 = = WebMaster@www.springer-ny.com = Springer-Verlag New York Inc. = 175 Fifth Avenue = New York, NY 10010 = TEL 1-800-SPRINGER = FAX 201-348-4505 = = Approx. price in US dollars is $135. = rgds,bro = P.S. Jim ... a BIG THANKS to you for telling us about this title ==== (4) ===== MDA Research Report #56 ========== Date : 04 May 95 17:41:38 EDT >From : Barry Goldberg <71154.330@compuserve.com> Subject: MDA Research Report #56 ---------------------------------------- It's been a while since the last MDA Research Report but here is the newest distributed just last week. I hope you find something of interest. For those with access to CompuServe, please take advantage of the extensive data files available as well as weekly conferences including a general conference at 8 PM Eastern and a new Parent's Conference on Mondays at the same time. Also under consideration is a weekly ALS Online Support Group. While INTERNET e-mail is welcome, the broadest information is through CompuServe at this time. There is no additional charge for the MDA Forum; only the $5.95 monthly fee and regular connect charges. I wish it could be available as no charge -- but I'm working on it! In the meantime, here's the research report as promised: April 21, 1995, Muscular Dystrophy Association ********************************************** MDA STAFF RESEARCH UPDATE -- SRU #56 MYOTONIC dystrophy (DM) affects a number of systems throughout the body. MDA researchers identified the genetic defect associated with DM as an unstable area of repetitive DNA within a particular protein kinase gene (DMPK or Mt-PK). The protein that is made from the information in this gene apparently has a function in many areas of the body, however, the reason that the expanded, unstable repeat causes DM is still not known. Scientists have thought that the extra DNA that is unstable may cause a mechanical problem in the expression of the DMPK gene. Gene expression refers to the process whereby a message is made from the gene and the message is sent to the machinery in the cell that can make the necessary protein. The expanded, unstable DNA in the DMPK gene may cause a problem when the gene is "read" to produce a message or when the message is "read" to produce the DMPK protein. Researchers have found plenty of DMPK message containing the repeats but the message does not seem to travel efficiently to the area where it can be read to make the protein. The conclusion is that individuals with myotonic dystrophy have plenty of DMPK message. However, whether the message can be used to make protein or whether the build up of the message interferes with other functions in the cell has yet to be determined. (Taneja, K. L. et al. Journal of Cell Biology 1995; 128:995-1002). Other research has shown that the repeat area of the DMPK gene appears to alter the structure of the DNA in such a way as to affect the expression of the DMPK gene or other genes in the region. (Wang, Y-H and Griffith, J. Genomics 1995; 25:570-573). In general, the severity of MYOTONIC dystrophy (DM) is associated with the size of the unstable DNA repeat in the DMPK gene. The larger the repeat, the more severe is the disorder. However, similar numbers of repeats have been found in individuals who are moderately or severely affected. In one family a child with congenital DM (repeat size=1100) and a child with late childhood onset DM (repeat size=1400) were born to sisters, having 300-400 repeats. There is discussion that factors other than repeat size may be involved in the development of the disease. In addition there can be considerable variability between the size of the repeat in lymphocytes versus muscle tissue. (Novelli, G. et al. Neuromuscular Disorders 1995; 5:157-159). CENTRAL CORE disease (CCD) is a myopathy that is closely associated with malignant hyperthermia (MH). One of the defective genes associated with MH is also associated with CCD. Generally, in families affected by CCD an individual who does not have signs of the disorder is not considered at risk for MH. However, a family was identified where several members were found to be susceptible to MH and they did not have signs of CCD. A test called the in vitro contracture test (IVCT) was used to identify the individuals who were susceptible. (Islander, G. et al. Neuromuscular Disorders 1995; 5:125-127). Clinical tests performed to diagnose the different forms of PERIODIC PARALYSIS can sometimes be inconclusive and this can lead to an inappropriate choice of therapy. Researchers experimented with laboratory analysis of excised muscle from various individuals to determine if such a test could differentiate between hypokalemic periodic paralysis (HypoPP), hyperkalemic periodic paralysis (HyperPP) and other diseases characterized by episodes of weakness. Results of the test on muscle tissue from people with clear diagnosis of either HyperPP or HypoPP demonstrated that these two forms of the disease could be differentiated. The scientists then tested muscle tissue from 13 individuals with unclear diagnosis. The test allowed them to diagnose 10 as HypoPP, 1 as HyperPP and the remaining 2 individuals had normal test results. The researchers conclude that laboratory analysis of muscle from individuals with unexplained attacks of weakness could be beneficial in determining the underlying cause of their symptoms. (Iaizzo, P. A. et al. Neuromuscular Disorders 1995; 5:115-124). One of the criteria for the diagnosis of FRIEDREICH'S ATAXIA (FA) is the absence of lower limb tendon reflexes. However, these reflexes are retained in a few individuals affected by FA and they have been classified as having FA with retained reflexes (FARR). Researchers in Italy performed genetic linkage tests on 6 families affected by FARR to determine the genetic relationship between FA and FARR. FA has been linked to a gene defect located on chromosome 9 and results from the genetic analysis showed that it is highly likely that the gene defect resulting in FARR is located in the same area of chromosome 9 as the gene defect causing FA. The researchers conclude that FARR is a variant of FA. (Palau, F. et al. Annals of Neurology 1995; 37:359-362). MDA researchers are studying ways to deliver adenovirus-carried genes to muscle in order to develop a gene therapy for DUCHENNE muscular dystrophy (DMD) and other neuromuscular diseases. How the gene is delivered is important as the method of delivery can influence the effectiveness of the gene therapy procedure. For example, the most efficient delivery of adenovirus-gene vehicles to the heart, diaphragm, intercostal muscles and thymus was attained after intracardiac injection. Whereas intravenous injection was the most efficient for delivery to the liver. However, a number of factors can affect the efficiency of delivery, such as the degree of blood flow to the tissue. Limb muscles have a relatively low blood flow and after any route of administration the efficiency of delivery of the adenovirus-gene vehicle is low. Scientists are working to identify the factors affecting the efficiency of delivery and to modify them for improved effectiveness. The researchers believe that the results demonstrating good delivery to tissues severely affected in DMD are promising. (Huard, J. et al. Gene Therapy 1995; 2:107-115). MDA researchers have shown that a variety of messages can be made from the large DYSTROPHIN gene. Not all genes make one message that dictates the formation of one protein, and in the case of the dystrophin gene there are apparently a number of different sized proteins that can be produced from the various gene messages. Some of these proteins are found in brain and muscle, another has only been found in nervous tissue and yet another is detected in a number of different tissues. Scientists have found a small version of the dystrophin protein (Dp140) that is produced from the important tail end of the gene and it is found in the central nervous system. When that area of the gene contains a defect it may result in the impaired cognitive functions sometimes associated with Duchenne muscular dystrophy (DMD). Dp140 is produced from the segments of the dystrophin gene that, when defective, appear to be more often associated with cognitive impairment. Further studies of the organization of the dystrophin gene and the particular functions of the various proteins produced from the gene are necessary before any conclusions can be made. (Lidov, H.G.W. et al. Human Molecular Genetics 1995; 4:329-335). OCULOPHARYNGEAL muscular dystrophy (OPMD) is a rare form of dystrophy that usually has an onset after the age of 50 and is characterized by droopy eyelids and swallowing difficulties. High-powered microscopic observation of OPMD skeletal muscle tissue shows a cluster of cylindrical filaments of certain sizes in specific parts of the cells. These filaments are specific for OPMD and can help differentiate the disorder from other myopathies and myasthenia gravis, however, the relationship of the filaments to OPMD is unknown. Genetic researchers have now linked OPMD to a particular region on chromosome 14 where they expect to find the defective gene associated with the disease. Interestingly the area contains genes for filamentous proteins and the researchers are studying these genes as well as other genes in the area for their possible involvement in OPMD. (Brais, B. et al. Human Molecular Genetics 1995; 4:429-434). LIMB-GIRDLE muscular dystrophy (LGMD) is a heterogeneous group of disorders that are becoming better defined through genetic research. The form of the disorder that was linked to chromosome 15 (LGMD2A) has recently been found to be the result of defects in a gene that contains the information for making a muscle protein called calpain 3. The function of calpain 3 is not completely understood although it is one form of several types of calpains that are known as enzymes. Enzymes are defined as proteins that are capable of causing chemical changes such as the breakdown of proteins or the acceleration of chemical reactions in the body. There is indication from the research to date that calpain 3 has a regulatory role and it may relate to the control of gene expression. The identification of the calpain 3 gene defects associated with LGMD2A should enhance the progress in determining the genetic causes of the other forms of LGMD. It is possible that other forms of calpain or other components involved in the same reactions that calpain 3 participates in could be defective resulting in clinically similar diseases. A number of different types of gene defects -- all of which would lead to a deficiency in calpain 3 -- have been associated with LGMD2A. Researchers studied small populations of related individuals who would be expected to contain the same gene defect, however, this was not the case. A French group of families from La Reunion were found to be affected by five different calpain 3 defects and most likely there are more defects involved. The geneticists are studying several possible genetic mechanisms that could explain such unexpected variation in the types of gene defects associated with related individuals. The unusual inheritance of the various LGMD2A gene defects may be the result of an, as yet, undiscovered genetic phenomenon. (Richard, I. et al., Cell 1995; 81:27-40). Additional heterogeneity was discovered in the analysis of the Indiana Amish LIMB-GIRDLE muscular dystrophy (LGMD) population. Affected families from northern and southern Indiana were clinically similar and some of the individuals were linked to the LGMD2A defect on chromosome 15. However, it was determined that six families from southern Indiana were not actually affected by LGMD2A despite their genetic relationship to the northern Indiana Amish who were found to contain defects in the calpain 3 gene. The unexpected inheritance patterns of LGMD gene defects have most likely contributed to the difficulties in the genetic analysis of this heterogeneous group of disorders. (Allamand V. et al., Human Molecular Genetics 1995; 4;459-463). END SRU_56.TXT * 04/21/95 (Research Update) cc: Bob Broedel -- ALS Interest Group [bro@huey.met.fsu.edu] --- MDA -- Working to find the cure for neuromuscular disease --- === end of als 191 ===