Alzheimers memory problems are caused by amyloid beta oligomers,not amyloid plagues

This is a single Alzheimer's disease plaque - the green shows fibrils and the red shows other assembly states of beta-amyloid;Image by Zerd via Flickr

Using a new mouse model of Alzheimer’s disease, researchers at Mount Sinai School of Medicine have found that Alzheimer’s pathology originates in Amyloid-Beta (Abeta) oligomers in the brain, rather than the amyloid plaques previously thought by many researchers to cause the disease.[2]

Alzheimer disease (AD) is the leading cause of dementia, affecting more than 26 million people worldwide.Clinically, the disease is characterized by progressive memory loss and a decline in cognitive abilities.[1]

Several symptomatic treatments are in use for AD; however, no disease-modifying therapies are currently available.[1]

The search for an Alzheimer drug is hindered by lack of understanding of the disease and also by the lack of suitable tests to measure efficacy of trial drugs.Currently the only way to measure efficacy in Alzheimer drug clinical trials is to use psychological tests which measure how well a patient is doing to how they were a year ago.There is quite a lot of variability in Alzheimer’s patients as to how they are doing mentally and there can be large variations in results.[3] Thus,in order to  to account for these variations the trials need to be conducted over many years.Imaging and immunoassays such as the ELISA assay are also used to see if the drug is working as expected.However these techniques alone are not enough as they measure physical processes such as antibody drugs binding to the target plagues which indicates if the drug is doing its intended while the mental tests discussed above tend to be quite variable in their own right which makes attributing changes in cognitive function to the drug challenging.

The study, which was supported by the  “Oligomer Research Consortium” of the Cure Alzheimer Fund and a MERIT Award from the Veterans Administration, appears in the journal Annals of Neurology.

Amyloids are insoluble fibrous protein aggregates sharing specific structural traits.Abnormal accumulation of amyloid in organs may lead to amyloidosis,something any fans of the TV show ‘House’ will be all too familiar with,and may play a role in various other neurodegenerative diseases such as Alzheimer’s.

Amyloid beta(Aβ or Abeta) is a peptide of 39–43 amino acids which appears to be the main constituent of amyloid plaques in the brains of Alzheimer’s disease patients and which also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,^[1] a protein fold that is shared by other peptides such as the prions associated with protein misfolding diseases.

“The buildup of amyloid plaques was described over 100 years ago and has received the bulk of the attention in Alzheimer’s pathology,” said lead author Sam Gandy, MD, PhD, Professor of Neurology and Psychiatry, and Associate Director of the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine. “But there has been a longstanding debate over whether plaques are toxic, protective, or inert.” [2,4]

Several research groups had previously proposed that rather than plaques, floating clumps of amyloid (called oligomers) are the key components that impede brain cell function in Alzheimer’s patients. To study this, the Mount Sinai team developed a mouse that forms only these oligomers, and never any plaques, throughout their lives.

In this case,oligomers refer to protein complexes composed of two or more subunits.Protein complexes are a form of quaternary structure with proteins in the complex being  linked by non-covalent protein-protein interactions.Different protein complexes have different degrees of stability over time and  complex formation often serves to activate or inhibit one or more of the complex members. In this way protein complex formation can be similar to phosphorylation. A method that is commonly used for identifying the members of protein complexes is immunoprecipitation.

The researchers found that the mice that never develop plaques were just as impaired by the disease as mice with both plaques and oligomers. Moreover, when a gene that converted oligomers into plaques was added to the mice, the mice were no more impaired than they had been before.

“These findings may enable the development of neuroimaging agents and drugs that visualize or detoxify oligomers,” said Dr. Gandy. “New neuroimaging agents that could monitor changes in Abeta oligomer presence would be a major advance. Innovative neuroimaging agents that will allow visualization of brain oligomer accumulation, in tandem with careful clinical observations, could lead to breakthroughs in managing, slowing, stopping or even preventing Alzheimer’s.[2]

“This is especially important in light of research reported in March showing that 70 weeks of infusion of the Abeta immunotherapeutic Bapineuzumab® ,a much anticipated humanized monoclonal antibody developed by Elan to bind to the plaques, cleared away 25 percent of the Abeta plaque, yet no clinical benefit was evident.” [2]

###

The Mount Sinai team included Michelle Ehrlich, MD, Professor of Pediatrics, Neurology, and Genetics and Genomic Sciences, and John Steele, a Mount Sinai graduate student, who performed the key analyses of the behavioral data. Dr. Charles Glabe, an oligomer expert and a member of the Cure Alzheimer Fund research consortium, is also a co-author of the paper. Dr Gandy is also a neurologist at the James J Peters Veterans Affairs Medical Center, an affiliate of Mount Sinai School of Medicine.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of few medical schools embedded in a hospital in the United States. It has more than 3,400 faculty in 32 departments and 15 institutes, and ranks among the top 20 medical schools both in National Institute of Health funding and by U.S. News & World Report. The school received the 2009 Spencer Foreman Award for Outstanding Community Service from the Association of American Medical

Colleges.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2009, U.S. News & World Report ranked The Mount Sinai Hospital among the nation’s top 20 hospitals based on reputation, patient safety, and other

patient-care factors. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and about 530,000 outpatient visits took place.

References

1.  http://www.medscape.com/viewarticle/717219

2.http://www.eurekalert.org/pub_releases/2010-04/tmsh-amp042710.php

3.http://health.nytimes.com/ref/health/healthguide/esn-alzheimers-qa.html

4.http://www.sciencedaily.com/releases/2009/11/091123114813.htm

Further Reading

Active and passive Immunotherapy for Neurodegenerative Disorders (pdf)

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A15416&rendertype=figure&id=A15420

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US Judge Rules That Gene Patents Are Invaild

BRAC1 Gene on Chromosome 17,Image via Wikipedia

In a powerful ruling a district Judge  for the Southern District of New York in the  US has ruled that patents on genes are invalid.Approximately 20 per cent of the human genome is currently subject to a patent.The judge,Robert Sweet,has overturned the patents on two genes linked to breast and ovarian cancer on the grounds that they’re not man-made, but products of nature. A company Myriad Genetics had previously patented the BRCA1 and 2 genes which were the subject of the ruling.They were charging women more than $3000 for one test for genetic mutations and banned them from getting a second opinion.

BRAC1 and BRAC2

BRAC 1 and 2 are human tumor suppressor genes that produce proteins which combine with other tumor suppressors to repair damaged DNA and destroy the cell if the DNA is unrepairable. Some inherited mutations in these genes lead to uncontrolled cell division i.e. cancer and testing for these mutations can determine the risk of contracting ovarian or breast cancer.

Court Case

The case was taken to court by the American Civil Liberties Union (ANLU) and individual breast cancer patients who argued that the patent stifled medical research.This ruling  follows much earlier rulings in Europe by the European Patent Office in 2004 which revoked Myraid genetics European patents on the BRAC1 and 2 genes ,effectively locking them out of the European market.However those patents were revoked because the charity Cancer Research UK had filed its patent on the BRAC2 gene first and the patent on the BRAC1 was deemed not ‘inventive’.

Previous Fate of Myriad Genetics Patents in Europe

The European Patent Organisation (EPO) had originally granted 3 patents on the BRCA1 gene (EP-B-699754, EP-B-705903, EP-B-705902) to Myriad Genetics. The patents, and the option by the patent holder to strictly exert its monopoly right by requesting that all diagnostic testing be done at its laboratory in the United States,evoked strong reactions throughout Europe. Several opposition procedures had been started against these patents. After oral hearings at the EPO in Munich in May 2004, the first patent was revoked due to discrepancies of about 10 DNA letters between the BRCA1 gene sequence described in Myriad’s patent, issued in 2001, and the sequence in Myriad’s original patent application on the gene in 1994.By the time that Myriad had resubmitted the correct sequence it was found that the sequence had already been openly published elsewhere-this is known as ‘prior art‘.This deemed it automatically unpatentable as inventions have to be original/ inventive to be patented.At oral proceedings in January 2005, the other two patents were also severely limited in scope.

Current Law on Gene Patents

Patents cannot be granted on things found in nature and logically you would think that genes would fall into the

nature category since they are not man-made.However, patents can be granted on gene sequences as long as these sequences are claimed in the form of ‘isolated DNA’,that is DNA which has been purified from the body.This practice is based on the view that DNA should not be treated any differently to another chemical compound and that its isolation from the body renders it patentable as it has been transformed into a different character.Supporters of gene patents look at this as getting a patent on identifying the gene and not on the actual gene.However many scientists in the genomics and molecular biology field consider this to be a ‘lawyers trick’ as it gets around the problem of patenting DNA in the body which cannot be done since it constitutes a component of ‘nature’,but which in practical terms produces the same results as if we had patented DNA in the body

Breast cancer associated protein, BRCA1.

US Court ruling

DNA is essentially the physical form of biological information,and is distinct in its essential characteristics from other chemicals found in nature. It is concluded that DNA’s existence in an “isolated” form alters neither this fundamental quality of DNA as it exists in the body i.e. in nature  nor the information it encodes. Therefore, the patents at issue which were on  “isolated DNA” containing sequences found in nature are unsustainable as a matter of law and are deemed unpatentable subject matter under 35 USC 101.

Also because the claimed comparisons of DNA sequences are abstract mental processes ,they also constitute unpatentable subject matter under Section 101

Comments

Myriad Genetics is likely to appeal this ruling so the story is far from over but its a nice step forward for research in this area.

References

Europe revokes controversial gene patent-New Scientist 2004

The European opposition against the BRCA gene patents.-Paper from Fam Cancer. 2006;5(1):95-102.

US Judge rules cancer gene patent invalid-abc.net.au

Court:Essentially All Gene Patents Are Invalid-patentlyO (patent law blog)

Human Genetics Commission

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Looking for Drug Information?

Image via WikipediaIntroduction

Introduction

I’m writing this post to give advice and include a list of links that I think will be helpful to any college students,businesses,individuals etc who have assignments on various drugs and their manufacturing to do. I know from experience it can be hard to find the exact information you are looking for and nearly impossible to find manufacturing processeses as the details of are generally closely guarded by the drug manufacturers.

Difference Between Generic and Patented Drugs?

One of the first things you may have to figure out is if your drug is still covered by a patent or if the patent has expired and it has now become an off-patent generic drug i.e. many different companies can make the same drug under different trade names.However don’t get confused into thinking a drug is a generic drug  if you see the phrase ‘generic name’ on websites.All drugs have generic names or International Non-Proprietary names (INN‘s),issued by the World Health organization (WHO), which are  the standard names for each drug.INN names are designed to be unique and distinct so as to avoid confusion in prescribing. A similar role is played in Chemistry by IUPAC names to name chemicals in a standard format.

For example,say you are looking for a drug called Panadol. Panadol is a proprietary name i.e. a name owned by someone, for the drug paracetamol which is a generic/INN name.In the United states paracetamol’s non-proprietary generic name is acetaminophen.The American name is known as the United States Adopted Name (USAN).USAN’s are the non-proprietary names that are assigned to pharmaceuticals marketed in the United States.

In summary,the generic name of Panadol is either paracetamol or acetaminophen based on where in the world you are (they are both the same drug).It is an off-patent drug/generic drug (as opposed to an on-patent/proprietary drug) and so it can be manufactured and sold by different companies (since the patent has expired) under various band names such as Panadol,Tylenol,Dolprone,Calpol, and a whole host of other names (see here for a list of paracetamol brand names on Wikipedia).It is also just sold under its generic names which are paracetamol or acetaminophen;it dosen’t have to be sold under a proprietary name.Other generic names for paracetamol are n-acetyl-p-aminophenol and p-acetamidophenol. Knowing the chemical name,other generic names and the formula of a drug are also useful for searching patents.

Sources of Information

Search Engine

Doing a general search using the tradename and then the generic name on search engines like google is a good first port of call.If the drug is marketed under more than one name its a generic drug,if not it is likely to be a drug still covered by a patent although make sure you havent missed any tradenames by accident.

FDA and EMEA websites

If the drug is approved for use in the U.S. and is a generic it will be on the FDA‘s list of generic drugs on their website which is updated on a quarterly basis.The Europen Medicines Agency(EMEA) ,which is the E.U equivalent of the FDA in America, publish European Public Assesment Reports(EPAR’s) on their website which contain summarys and detailed discussions on drugs approved in the E.U. (access list of EPAR’s here).The Scientific Discussions they publish as part of these EPAR’s are also particularly useful as they often contain a brief section on manufature and quality control tests that will be ran on the drug as well as clinical trial data and pharmacology.Just click on the link for the drug you want to learn more about and then click on the individual icon under your selected language (EN) to read the contents.

The ‘Orange Book’

The ‘Orange Book’ is another resource that is available to search on the FDA website (access here) and it can be searched by active ingredient,patent holder, proprietary name,applicant holder and application number.It will provide information on a multitude of different dose forms of various drugs as well as whether or not the drug is on an unexpired patent (propitierary) or not (generic).

Prescribing Information

Getting the Prescribing Information of a drug is also a must,many sites like Rxlist.com provide this kind of data or it can be found on the website of the drug or the company website.

Product Monograph

Product monograhs are a great information source and will often contain more than the prescribing information.However they can be harder and sometimes impossible to find!Good places to start looking are the website of the drug,the company website,by typing the name into google with the words ‘monograph’ or ‘product monograph’ after it.The AHFS website also publishes a book called AHFS Drug Information which describes many drugs.

Pharmacopeias

Pharmacopoeias are a good source of well referenced drug information and iclude data on toxicology,pharmacology ,uses,physical and chemical data and tests to identify the drug.

Patents

For information on the manufacture of a drug you are in most cases going to have to find the patent or patents for the drug.Good places to start looking are the ‘advanced search’ sections of Free Patents Online,Google Patents and patent abstracts at the EBI.If searching by company name (assigne name),check first to see if the company was previously called anything else or it the the company that now sells the drug acquired the company that holds the patent.If any other company names are associated with the drug search these too.Don’t forget to look at related patents too;these are named on the title page of the patent usually and will be referenced in the text also.

Many of the websites named in this text are also listed in my ‘Resources’ links for ease of access.If anyone knows any other resources that they think would be of use to others,please leave a comment about them!

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