[2003] - Retinoids as candidate targets for alzheimer’s disease treatment (Target of the Month, TherapeuticAdvances, April, 2003)
Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving value of this therapeutic class to over US$1.2 billion in 2001. Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the amyloid protein, trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation.
The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other diseases has been limited. In our recent dossier "Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" (click here for access) we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.
As our understanding of the retinoids increases so do their therapeutic indications. For example COPD and obesity have both recently emerged as targets for retinoic acid receptor ligands. Most recently Boston based researchers have put forward the hypothesis that late onset AD is influenced by the availability in brain of retinoic acid. This hypothesis is based on a body of genetic, metabolic, and environmental/dietary evidence. For example, significant genetic linkages to AD are demonstrated for markers close to four of the six retinoic acid receptors; three of the four retinol-binding proteins and the retinoic acid-degrading cytochrome P450 enzymes (for further information on each of these proteins and retinoid pathways go to our retinoid dossier). Retinaldehyde dehydrogenase (RLDH), the enzyme that forms retinoic acid from retinaldehyde, was present in hippocampus, frontal cortex, and parietal cortex, and its activity in the hippocampus and parietal cortex of Alzheimer diseased brains was 1.5- to 2-fold higher compared to controls. In contrast, the RLDH activity of frontal cortex was the same for both Alzheimer diseased and control groups.
Retinoid responsive transgenes have been shown to be highly active in the hippocampus and the activation of such genes has been reported to facilitate neurotrophin-induced maturation of stem cells into neurons. While retinoic acid may be important in neurogenesis, defects in the retinoid pathway may lead to impaired neurological function. This is supported by data showing that retinoid receptor expression is reduced in aged mice and that this is related to behavioral deficits consistent with diminished cognitive function. This could be reversed by retinoic acid treatment. This and the genetic/molecular evidence linking the retinoids to Alzheimer’s disease suggests that retinoic acid or its mimics may represent a useful approach to the treatment of cognitive disorders. Of particular interest to the treatment of Alzheimer’s disease it has been shown that the reductions in acetylcholine content caused by Abeta42 could be prevented by a co-treatment with retinoic acid.
On the other hand however, evidence is also available to suggest that retinoic acid can increase secreted Abeta40 and Abeta42. Of interest the response was biased towards the latter, more cytotoxic form of beta amyloid. Careful drug design could therefore conceivably lead to the development of a treatment that both improves cognition and also limits the suggested underlying cause of Alzheimer’s disease.
With the advent of improved models of Alzheimer's disease as well as a greater inventory of pharmacological tools able to probe retinoid biology, further studies designed to probe this provocative link between the retinoids and AD are eagerly awaited.
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Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development
The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. Retinoids in current use are effective in only a small number of cancers as well as acne and psoriasis. Extending this benefit to other types of cancer as well as newer indications such as diabetes and airway inflammation has represented a hurdle that will only be fully overcome by taking into account the biology of the retinoids. LeadDiscovery’s "Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" represents one of the most comprehensive insights into the retinoid field published in recent years. The aim of this report is to bring the reader up to date with advances in this area, pharmaceutical activity relating to retinoid development and strategies that will lead to the identification of improved retinoids.
Available retinoids are effective in treating acne and psoriasis. Likewise the retinoids are also beneficial in the treatment of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma and cutaneous T cell lymphoma. This has led to the launch of Ligand Pharmaceuticals' three marketed retinoids Tagretin gel, Tagretin capsules and Panretin which are indicated for T cell lymphoma or Kaposi's sarcoma. Although the incidence of these cancers is relatively low Ligand's retinoids generated sales of $57 million in 2002.
Although numerous cancers are associated with alterations in retinoid biology, clinical efficacy of retinoids has been limited - understanding why, and how this "resistance" can be overcome therefore represents a major goal in oncology. Meeting this goal will extend the therapeutic benefit of the retinoids to other major cancers as well as other newer indications for the retinoids such as diabetes and COPD. These advances would be attractive both clinically and commercially.
Early clinical studies and retinoid development commenced without an understanding of retinoid molecular biology. It is now clear that the actions of these molecules are, in almost all cases, via their nuclear receptors, whereby they are able to impinge on the expression of multiple genes. It is therefore not surprising that a "shotgun" approach to the retinoids has generally produced disappointing results in the clinic.
"Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" takes the reader on a journey through the various field of retinoid biology and is designed to offer an insight into how the retinoids confer specificity under physiological conditions; the pathophysiology of the retinoids; and pharmaceutical strategies that may increase the therapeutic benefits of the retinoids. In particular the report overviews biochemical and cellular pathways controlling retinoid uptake retinoid synthesis and metabolism the biology of the various proteins that shuttle the retinoids from cell to cell and onwards to their site of action the various retinoid nuclear receptor complexes their ligands and their interaction with the genome modulation of nuclear receptor-conferred control of transcription by co-repressors and co-activators
the role of the retinoids in the pathophysiology of cancer as well as animal and clinical data surrounding the therapeutic use of the retinoids retinoids in development or on the market One of the main focusses of this report is the regulation of gene expression by nuclear receptor dimers and how plasticity has evolved within this system. The RXR receptor has emerged as a key binding partner, forming dimers with RAR receptors as well as members of the other nuclear receptor families. Each dimer is able to bind a specific set of DNA response elements, and the multiplicity of isoforms and splice variants of each receptor therefore introduces a basic level of plasticity. Therefore during the drug development process one is faced with the choice of advancing molecules with mixed or selective activity. Since a large number of receptor subtypes exist, it is possible to adopt the middle ground - for example, Allergan have developed Tazarotene, which was the first of a new generation of receptor-selective retinoids targeting RARb and RARg.
The make-up of a particular dimer not only determines which genes it can influence, but it also determines which of the many co-regulatory molecules it may bind. Paralleling the "histone code" the large number of possible dimer/co-regulatory complexes adds a further level of plasticity, through what has been termed the "co-factor code". Challenges of the future will include the selection of gene targets and the identification of dimer-co-regulatory complex(es) that play a role in the control of these genes. This report provides a full inventory of known co-regulatory molecules. Advances in genomics are allowing gene expression profiles to be identified for particular disease states and gene targeting is already aiding the drug development process. It is now hoped that the identification of dimer/co-regulatory complexes able to regulate the expression of these target genes will soon become a common feature of therapeutic development.
Table of contents
Background
A (very) early history of the retinoids
From liver to “fat soluble factor A”
Identification and early functional characterization of vitamin A
Basic retinoid metabolism
Vision and the retinoids
Bioavailability of retinol
Intestinal absorption of retinol
Retinyl ester formation
Retinoids mobilization, storage and delivery
Retinyl esters and chylomicrons
Retinyl ester uptake by the liver
Retinyl ester hydrolysis in the liver
Bile-salt-dependent retinyl ester hydrolase (carboxylester lipase)
Bile-salt-independent retinyl ester hydrolases
Retinyl ester storage in the stellate cells of the liver
Retinoids delivery to and between target cells
Retinyl esters and chylomicrons
Retinol and plasma retinol-binding protein
b-Carotene and retinyl esters and plasma lipoproteins
Retinoic acid and albumin
The interphotoreceptor (or interstitial) retinol-binding protein (IRBP)
The epididymus retinoic-acid binding protein (E-RABP)
Cellular retinoid-binding proteins
The cellular retinol-binding proteins (CRBPs)
The cellular retinoic-acid-binding proteins (CRABPs)
The cellular retinaldehyde-binding protein (CRALBP)
Retinoic acid
Retinoic acid biosynthesis
The early ideas
The alcohol dehydrogenase family
The short-chain dehydrogenase/reductase family
The aldehyde dehydrogenase family
The cytochrome P450-dependent monooxygenases
Retinoic acid and beyond
Retinoic acid catabolism
The retinoid receptors
The nuclear receptors
The retinoid receptors
The retinoic acid receptors
The retinoid X receptors
The RARs and RXRs as nuclear receptors
Synthetic retinoids
The retinoids and transcriptional activation
The retinoids response elements
Autoregulation of retinoid signaling
Dimerization for activation
RXR/RAR heterodimers
RXR homodimers
Further RXR heterodimers
Specificity within RXR/RAR heterodimers
Structural determinants for dimerization
Co-regulators and transcriptional activation
General transcription factors
Pre-initiation complex assembly
Further transcriptional processes
Initiation
Promoter clearance
Transcript elongation
Transcriptional termination
Non-nuclear-receptor transcriptional co-regulators
Nuclear receptor co-activators
Nuclear receptor co-repressors
General co-regulator considerations
The retinoids and cancer chemoprevention
General introduction
Statistical information on incidence of major cancers
Treatment options for major cancers
The retinoids connection
The retinoids and cancers
Skin cancer
Oral cancers
Head and neck cancers
Breast cancer
Lung cancer
Pancreas cancer
Liver cancer
Prostate cancer
Bladder cancer
Colorectal cancer
Renal cancer
Ovarian cancer
Thyroid cancer
Blood cancers
Some specific mechanisms behind retinoid action
Retinoid receptor co-regulator recruitment: further structural considerations
The retinoic acid receptor b (RARb)
The transcription factor AP-1
Apoptosis, 4-HPR, and CD437
PPARg/RXR in diet-induced obesity and type 2 diabetes
Research tools
Reference retinoids used in research
Methodologies
An overview of current development activity
Profiles of molecules developed as regulators of retinoid acid biology including
adapalene (CD271)
AGN-194310
AGN-195183
alitretinoin (9-cis-retinoic acid)
bexarotene (Tagretin, LG-1069)
etretinate (Tigason, Ro 10-9359)
fenretinide (4-HPR)
isotretinoin (13-cis-retinoic acid)
LGD-1550
MDI-101
MDI-301
MDI-403
motretinide (Ro 11-1430)
PLT-99257
PLT-99511
R-667
rambazole
RARß2 gene therapy
tazarotene (AGN-190168)
tocoretinate
tretinoin (all-trans-retinoic acid, vitamin A acid)
UAB-30
Companies involved in retinoid biology
Publication date: Febrary, 2003
About the contributors to this report
Dr Chris Berrie: Dr Chris Berrie has been working in a range of developing research areas for over 20 years, from receptor biochemistry, through second messenger signaling, towards signal transduction pathways in cancer cell biology. These have been in both governmental and academic research laboratories and within Smith Kline and French Research, and Dr Chris Berrie has co-authored some 50 peer-reviewed research publications. More recently, these have included book chapters (such as in Molecular Mechanisms of Signal Transduction and the Encyclopedia of Molecular Medicine), a FASEB Journal research hypothesis, and two overviews in Expert Opinion on Investigational Drugs and in a special review edition of Biochimica et Biophysica Acta. Dr Chris Berrie has now taken on a Freelance writing role in the LeadDiscovery production of DiscoveryDossier Therapy Overviews.
Dr Jon Goldhill: Dr Jon Goldhill has over 10 years of academic and industrial research experience including 5 years in middle management at the French pharmaceutical giants, Sanofi-Synthelabo. Focussing on a variety of indications including inflammatory disorders, GI disease, Urological conditions and cancer, Dr Goldhill was responsible for target identification and project development. Dr Goldhill is now CEO and chief analyst at LeadDiscovery and coordinates the identification of candidate drug discovery projects with industrial potential.
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