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Researchers have just begun to address the idea of developing multiple-gene targeted drugs for multiple-gene targeted diseases.  Single-gene targeted drugs, like Herceptin, Iressa and Erbitux have been met with disappointment.  A discussion regarding the development of such drugs is published in a recently published edition of Expert Opinion in Drug Discovery.

The ability of these drugs to avoid polypharmacy (when too many forms of medication are used by a patient) is a desired secondary objective.

But in saying that, multiple-gene targeted drugs are also anathema to pharmaceutical companies that have been financially built on the false premise of one drug for each disease.

While these researchers suggest modern pharmacology switch direction and develop multi-gene targeted drugs, for now, modern medicine is dragging its feet over this idea.

Multi-gene targets would address many diseases at one time, including the aging process itself that is responsible for most of the chronic disease experienced by adults with advancing age.  Pharmaceutical companies would be putting themselves out of business.

These researchers say:  “while this approach (single-gene targeted drugs) remains the mainstay drug discovery concept at most companies, several groups have started work on the development of compounds that will simultaneously modulate two or more drug targets in the disease process.”

Other researchers say: “Traditional drug discovery strategies ignore the complexity of biological systems, screening compounds on individual targets rather than focusing on bio-molecular networks. Despite growing evidence that the conditions we aim to treat are complex and require the development of treatments that exhibit poly-pharmacological properties, current drug discovery programs still rely on simplistic approaches during compound selection.”

Scientists are just now announcing they have actually developed designer drugs that exert influence over multiple gene targets to address complex diseases.  But natural molecules do this demonstrably better at far less cost, and natural molecules are not totally unproven as synthetic drugs are.

Resveratrol targets many genes

The most widely studied multiple-gene targeted molecule, resveratrol, is largely being ignored in cardiology, ophthalmology, oncology and neurology even though it is widely available as a dietary supplement and relatively safe in modest doses.

There are many other natural small molecules that also target multiple genes.  To make them blockbuster drugs they must be altered into a synthetic molecule so that patents can be gained.  In doing so, they may perform no better or even be less effective than existing natural molecules.

An example of the superiority of natural molecules can be found in the medical literature.  The ability of resveratrol (rez-vair-ah-trol), known as a red wine molecule, to regulate a broad number of genes was demonstrated in 2008 when it was shown that short-term/long-term resveratrol use activated 225/831 genes in laboratory mice, but a combination of resveratrol plus other small molecules (Longevinex®) differentiated 1711 genes over a short-term!  What would normally take a lifetime for plain resveratrol to do in a laboratory mouse was accomplished in just a few weeks!

This is the most phenomenal demonstration of small molecules to exert influence over a broad number of genes in a global analysis of the rodent genome, which is about the same size (~25,000 genes) as the human library of genes.  However, this discovery is only cited 8 times in other published papers.  For unexplained reasons, it is being ignored.  Its discoverers don’t even lecture about it.

The fact that more than half of human genes are redundant or inoperable (pseudogenes) narrows the number of genes needed to exert significant influence.  Furthermore, genes are connected in networks and there are so-called upstream genes that affect many other downstream targets, which suggests a small number of genes may control a broader number of genes.  Researchers have determined just 295 genes are involved in human aging.  So the ability to conquer aging with within reach, at least genetically.

In the aforementioned animal lab experiment, Longevinex® switched 677 of 831 genes (81%) in the same direction as a calorie-restricted diet, a dietary regimen that is widely known to double the lifespan of all living forms of life.  For comparison, plain resveratrol switched less than 20% of these same 831 longevity genes.

An example of a key gene that activates other genes is NF-Kappa B, a gene that controls the immune response and targets many other downstream genes.  Inhibition of NF-Kappa B actually reverses some aspects of aging.  Resveratrol is known as a potent inhibitor of NF-Kappa B.

By developing multi-gene targeted drugs pharmaceutical companies could be committing financial suicide, that is unless they can convince their new mega-pill can replace five current drugs to justify billing insurance $65 a day!

Some biologists propose use of multiple synthetic molecules in a single drug to achieve the broad genetic effect needed to combat multi-genetic diseases, something that has already been demonstrated by Longevinex®.

Longevinex® has already been demonstrated to reverse a blinding condition in humans, turn mortal heart attacks into non-mortal events in animals (for ethical reasons, this cannot possibly be demonstrated in humans) and theoretically inhibits new blood vessels that feed tumors better than current anti-angiogenic drugs like Avastin.

Over a decade ago modern pharmacology first attempted to introduce so-called personalized medicine where drugs are matched to address the specific gene mutations found in each individual.

Multi-gene targeted drugs don’t address the static structural flaws in genes (mutations), but rather the dynamic protein-making properties of genes (called epigenetics) that switch genes on and off (called gene expression and gene silencing).

Not only is the idea of personalized medicine likely to be unaffordable, gene mutations only represent ~2% of all disease whereas epigenetics involves all disease.

The idea of personalized medicine appears to be another misdirection.  Every human has the same set of genes, though they don’t develop the same diseases, which suggests environmental factors (epigenetic factors such as diet, radiation, temperature) rule rather then gene mutations.

To produce multi-billion dollar blockbuster drugs that target multiple genes, modern pharmacology needs to ignore what has already been accomplished with natural molecules.  Will the public catch on to the ruse?  — Copyright 2012 Bill Sardi  ResveratrolNews.com

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Expert Opinion Drug Discovery 2012 Dec 12. [Epub ahead of print]

Designing drugs with multi-target activity: the next step in the treatment of neurodegenerative disorders.

Geldenhuys WJ, Van der Schyf CJ.

Source

Northeast Ohio Medical University, College of Pharmacy, Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences , Rootstown, 4209 State Route 44, P.O. Box 95, OH 44272 , USA +1 330 325 6467 ; +1 330 325 5936 ; cvanders@neomed.edu.

Abstract

Introduction: Neurodegenerative diseases have had devastating effects on patients’ quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such “multi-targeted designed drugs” (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses. Areas covered: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena. Expert opinion: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics.  PMID: 23231597