Would-be wonders

What potential blockbuster gene patents are waiting to be exploited by universities? Steve Farrar reports on eight that could make the grade.

HSP 90 gene Treatment of candida infection WO9100351, January 1991 Manchester University

Late last year, three patients at the Manchester Royal Infirmary and one at nearby Wythenshawe Hospital received doses of a white powder that heralds a new way to tackle infection.

Having completed safety tests, the drug - Mycograb - is ready for full clinical trials. For James Burnie and Ruth Matthews, microbiologists at Manchester University, a 15-year project to turn promising research into a practical therapy is entering a particularly exciting phase.

Mycograb bolsters the body's natural immune system with synthesised antibodies targeted to fight specific infections. Those first patients were given a treatment for candida, the fungal infection responsible for thrush and other, more serious illness. Last year, it killed 1,200 people in the United Kingdom. Many of its victims had weakened immune systems as a result of other illnesses or treatments - Candida albicans is a common hospital bug.

Burnie and Matthews looked at the natural antibodies produced by people who had fought off candida infection. They sought to isolate the antibody that targeted a fungal gene called heat shock protein 90. Their patent covers this gene in five different species of yeast and fungi, including Candida albicans . Mycograb is in essence concentrated antibodies, produced by fermentation using genetically modified E. coli bacteria.

NeuTec Pharma, a spin-off company backed by £7.3 million of venture capital, will exploit the research, and about £4.5 million has been pledged for a manufacturing facility.

S gene Therapy for psoriasis WO0058506, October 2000
Leicester University and King's College, London

The touch of the S gene leaves a painfully obvious mark on its victims - the red, flaky skin of psoriasis. Yet this common, chronic condition has no simple genetic root.

Genes other than the one identified by Richard Trembath, professor of medical genetics at Leicester University, and Jonathan Barker at King's College London have been strongly linked to the disease. And it seems that the environment about those genes is equally important in determining whether or not an individual gets the complaint.

Nevertheless, finding a gene strongly linked to psoriasis susceptibility raises the prospect of new therapies for a disease that afflicts millions. Trembath chased his gene through the generations. He recruited families with psoriasis sufferers, particularly sibling pairs, for wholesale genetic screening. The aim was to identify those genes that the family members with psoriasis were more likely to share.

From the statistical analysis emerged the S gene. This gene is found in a region of chromosome 6, which harbours genes that play a central role in the immune system. It produces a protein called corneodesmosin and is "turned on" only in the skin. The S gene offers insight into the causes of psoriasis as well as a tempting target for drugs to tackle the disease. Trembath's research has appeared in The Lancet . His patent covers 28 genetic sequences linked to the S gene and ways to use them to diagnose susceptibility and develop treatments.

Fragments of cal reticulin and factor H Innate immune system WO9848014/WO9823638, June/October 1998 Leicester University

A new way to boost the body's innate immune system could stop opportunist infections from claiming the lives of organ transplant recipients, chemotherapy patients and others, such as people with Aids, whose natural defences have been weakened.

At Leicester University, Wilhelm Schwaeble has been exploring the function of this basic biological defence mechanism that is shared by many organisms, both plant and animal. The innate immune system uses simple molecules to "check" the sugars found on the outer coating of microbes. Those that are not recognised are set upon immediately, ultimately prompting the invaders' destruction.

Schwaeble recognised that although the innate system is less sophisticated than the acquired immunity system - which deploys antibodies and specialised cells against specific infections - it could be easier to boost and could have many applications. For the transplant patient whose immune system has been artificially dampened to stop the rejection of a new organ, this could provide the crucial compensation to keep them free of infection.

Two patents cover ways to use the advance to fight infections and to target tumours. They include five genetic sequences relating to two genes that play a key role in innate immunity - factor H and cal reticulin. Schwaeble's pioneering work, funded by the Wellcome Trust, has progressed to laboratory testing and the creation of protein supplements. There is no commercial involvement yet, and clinical trials are a way off.

Various coding sequences Transgenic fish that produce human proteins WO98156, April 1998 Southampton University and Royal Free campus, University College London

The fish in Norman MacLean's laboratory do not look capable of worrying shrimps, let alone sheep. Nevertheless, these transgenic tilapia could pose a threat to the utility of Dolly and her ilk.

Scientists at Southampton University and the Royal Free campus, University College London, are genetically engineering the fish to produce human proteins for new pharmaceuticals. They are similar to the Roslin sheep that have been engineered to provide sources of human proteins.

The idea is to engineer animals to carry human genes that produce the required proteins. MacLean's fish have several advantages over their larger, land-dwelling counterparts. They are easier to engineer, faster to breed and cheaper to feed, and they could also be safer - there are no known fish prion or viral pathogens that can afflict humans.

The patent, filed by MacLean, professor of genetics at Southampton, and three colleagues, covers how to create the human protein-producing fish.

Fish that produce human coagulation factor VIII, a protein used to treat haemophiliacs and, potentially, accident victims, have already been created successfully.

The worldwide rights to license the technique have been acquired by US biotech firm AquaGene, which is honing the technology before seeking a commercial partner to take a product to the market.

Sox-9 gene Regeneration of bone and cartilage WO9617057, June 1996 Cambridge and Queensland universities

People with arthritis and injured athletes could benefit from drugs that regenerate cartilage in damaged joints. This is the goal of an effort to harness the Sox-9 gene.

The gene was found in the mid-1990s by Peter Goodfellow, professor of genetics at Cambridge University, when the patent was filed, and Peter Koopman, a molecular biologist at the University of Queensland, Australia.

Their initial observations, later confirmed by other researchers, suggested that Sox-9 - one of a family related to the sex-determining gene SRY - was needed to turn undifferentiated cells into specialist cartilage-producing cells. The connection was made while studying the central role the gene plays in forming a temporary cartilage skeleton in the embryo that later develops into bone.

It was subsequently found that mutated versions of Sox-9 lay behind a rare and complex disorder called campomelic dysplasia, which afflicts its infant victims with skeletal and developmental defects that usually lead to a very early death. The scientists speculated that it may be possible to produce a drug that influenced Sox-9 function. This could tackle degenerative conditions such as arthritis as well as injuries by boosting cartilage formation.

Cambridge and Queensland backed the initial patent application covering 21 genetic sequences connected to Sox-9 and techniques linked to this type of therapy. The patent has since been taken on by Research Corporation Technologies, a US firm that brokers such technology, gaining full patent status in the US. The technology now awaits a company prepared to turn the science into a product.

Intron between tRNA genes for leucine in cannabis Illicit drug detection WO9824929, June 1998 Strathclyde University

The genetic fingerprinting of cannabis may allow law enforcement agencies to track shipments back to their origins. It would give the authorities a way to uncover illicit supply routes and distribution networks.

This was the premise that Adrian Linacre, a forensic scientist at Strathclyde University, began exploring in the mid-1990s. Yet the project he has focused on in the past four years is somewhat less ambitious - a quick and easy test to determine if a substance is cannabis.

The patent centres on a genetic sequence that is not a gene. It is an intron, a sequence of DNA that, in this case, separates two tRNA genes in the plant's genome. Linacre found that the intron he isolated was common to all cannabis but is apparently not possessed by any other green plants. The test he has devised gives a positive result if it detects the genetic sequence in the sample. It is simple and fast in comparison with chemical tests used by police and Customs and Excise officers.

Strathclyde covered the cost of the research and patenting, but it needs commercial partners to turn the test into a product. The university is seeking candidates.

A genetic construct including a blood-clotting gene
Treatment of haemophilia WO9428151, December 1994 Royal Free campus, University College London, and the Medical Research Council

Haemophiliacs could be protected against profuse bleeding by an annual gene therapy injection. Researchers at the Royal Free Hospital School of Medicine, London, have devised a way to supply the body with the blood-clotting protein Factor VIII.

People with Haemophilia A, which affects one in 5,000 male births, have a defect in the gene that codes for this protein. As a result, their wounds do not stop bleeding as they would in a healthy person, and they also suffer damage to joints and internal tissues. They can be treated with Factor VIII concentrated from donated blood, but this carries the risk of contamination with infectious agents. And manufactured clotting protein is expensive and must be regularly administered.

Geoffrey Goldspink, professor of anatomy and developmental biology and chairman of basic medical sciences, and Christine Lee, director of the Haemophilia Centre, both at the Royal Free campus, University College London, have created a gene therapy technique in which a haemophiliac would receive a single annual injection into muscle cells.

The pharmaceutical carries the Factor VIII gene linked to other engineered sequences. This enables the cells to produce the clotting protein, which the bloodstream can distribute. The technique and engineered sequences are covered in a patent application taken out by Goldspink and two colleagues.

Beta 3 sub-unit VGSC gene Epilepsy, pain relief and heart murmurs WO0063367, October 2000 Cambridge University and Warner Lambert

Drugs that could relieve chronic pain, quell heart murmurs and prevent forms of epilepsy might emerge from research into a single gene.

The gene was traced through tests that Kevin Morgan, a member of the Cambridge University team, admitted were initially speculative. The scientists cultured two almost identical rat neurotransmitter cell lines, one of which had a single biochemical defect in the way it generated electrical pulses. When they compared which genes were "switched on" in the two cell lines, one gene - the Beta 3 sub-unit of the voltage-gated sodium channel gene - emerged. This gene is thought to be one of a handful that combine to control electrical impulses in living cells.

Over the past two years, the project has received £200,000 from the US drug company Parke-Davis, whose parent company, Warner Lambert, shares the patent with Cambridge University, Morgan and three colleagues. The prospect that the discovery could be exploited to help design drugs to tackle conditions linked to the nervous system made it an attractive commercial proposition. But Pfizer's purchase of Parke-Davis and its decision in November not to sign an exclusive licensing agreement with the university have left the project seeking a new industrial partner.