BBI

Poliomyelitis (polio) is a highly infectious disease caused by a virus that multiplies in the intestine, invades the nervous system and can cause total paralysis in a matter of hours. One in 200 infections leads to irreversible paralysis (usually in the legs), and among those paralyzed 5% to 10% die when their breathing muscles become immobilized. The disease mainly affects children under five years of age. There is no cure for polio, only prevention. Oral vaccination given four times during the first year can protect a child for life.

So here is the good news. The World Health Organization (WHO; Geneva, Switzerland) launched in 1988 a global initiative to eradicate polio by 2000. Although there has been some slippage in the program timing, the number of cases over the past 14 years has fallen by more than 99.8%, from an estimated 350,000 cases in 1988 to 537 last year. Today polio is only found in parts of Africa and south Asia. The three zones with the highest poliovirus transmission risks are northern India, Afghanistan/Pakistan and Nigeria/Niger.

The Global Polio Eradication Technical Consultative Group, which is continuing its program with mass immunization campaigns, has said that the biggest threat to the eradication initiative is now the funding gap. Substantial donations from Canada, Japan, the Netherlands, the United Kingdom and the United States have reduced this gap to $275 million over the past year.

Rotary International helped to spark this global movement in 1985 when it launched its first fundraising drive with the goal of immunizing every child throughout the world against polio by its 100th anniversary in 2005. "Now that we are approaching our goal, we need just $275 million to finish the job," said Luis Vincente Giay, chairman of the Rotary Foundation of Rotary International. "If we raise this money now, we will be saving all of humankind from this disease for all time, and that's priceless."

The Pasteur Institute (Paris) has set up a program with Novirio Pharmaceuticals (Montpellier, France) to evaluate the company's extensive library of compounds for antiviral activity against a deadly group of viruses that cause hemorrhagic fever. These include the Ebola, Marburg and Lassa fever viruses.

The hemorrhagic fever virus (HFV) research project is intended to combine the resources of the Pasteur Institute, renowned as one of the world's leading infectious disease research centers, with Novirio's novel drug discovery approach. "The threat of an outbreak of one of these deadly viruses is of immense importance since there are no vaccines or effective treatments currently available," said Jean-Pierre Sommadossi, chairman and CEO at Novirio. "Some of the viruses targeted by our collaborative efforts, such as Ebola, have been the source of disastrous epidemics in remote regions of the world. Now, in the face of bioterrorism, even the most developed areas of the world must maintain a greater level of preparedness against the threat of HFV infections and disease."

Separately, Novirio has won a $1.6 million award from the European Commission to fund a project to develop drug candidates for the treatment of flaviviruses including hepatitis C, dengue fever and West Nile viruses. The project, called Flavitherapeutics, also involves research teams in France, Italy and Germany.

Not-so-good news are high rates of HIV/AIDS infection in southern African countries that are adversely affecting their economies, with Botswana being already under threat. The country's 1.7 million population has the highest HIV/AIDS infection rate in the world, with an estimated 38% of the sexually active population (ages 15 to 49) being HIV-positive, according to the latest Ministry of Health figures. Tuberculosis infections have tripled over the past decade and now account for 30% of AIDS-related deaths.

"HIV/AIDS is the greatest challenge Botswana has faced and threatens the country with annihilation," said President Festus Mogae. He said that the pandemic was not abating, in spite of the government's efforts to counter the spread of HIV/AIDS through prevention and treatment campaigns. He said the country faced severe shortages of health professionals to tackle the disease and had already suffered a decline in economic growth.

The Bank of Botswana forecasts economic growth this year of only 5%, sharply down from 9% in 2001. A government study predicted last year that economic output would fall by 1.5% annually over the next 25 years, while health expenditure would treble over the next 10 years. By the end of this year, Botswana expects to have four antiretroviral drug-dispensing centers in operation, with 19,000 patients on state-funded treatment. Some companies have also have responded to the problem by providing antiretroviral drugs to their employees. Debswana, the main diamond producer, pays for 90% of its employees' costs should they need to take anti-retrovirals.

The pandemic also is affecting South African mining groups with large workforces. Chris Thompson, chairman and CEO of Gold Fields, a major mining company, said 26.5% of its 50,000 workers were HIV-positive and that the high level of infection added as much as $10 to the cost of producing an ounce of gold. He said the company's strategy to combat HIV/AIDS through prevention and treatment would reduce the extra production cost to about $4 an ounce, with an average annual output of about 4.5 million ounces.

Bone replacement marketing problems

Whereas in the United States the FDA has acknowledged the unique nature of tissue-engineered products and has introduced a new regulatory program for them, in Europe there is no control at the European Union (EU) level, but instead varying national approaches exist which act to make marketing and distribution complicated and difficult. Manufacturers of human tissue products, including autologous tissue-engineered components, will have to ask for approval at differing national levels in each member state.

In some countries such products can only be imported through a tissue bank. In others, pharmaceutical regulations apply, and in others again no regulations currently exist but are likely to be developed soon in the absence of European Union regulation. The inconsistency in regulating emerging therapies, such as autologous tissue engineering, has created confusion in potential suppliers and further creates a difficult environment for the consistent and safe development of human tissue products. While the U.S., Canada and Australia each have defined regulatory programs based on risk-benefit analyses, to date no decisions have been made by the European Commission.

A typical example is VivescOs, a living bone product for bone replacement produced by IsoTis (Bilthoven, the Netherlands). A bone marrow aspirate is taken from the patient's pelvic bone and the cells are expanded. When sufficient cell numbers have been achieved, they are seeded onto a suitable biomaterial scaffold and stimulated to form a bone matrix. The implant, made from the patient's own cells plus biomaterial scaffolding, can then be implanted.

For this company located in the Netherlands, since there is no Dutch mandate to inspect a human tissue production site, but there is a trade barrier with Germany and Austria, both of which demand a GMP compliance certificate. In Belgium and Spain, importation must be through a local tissue bank, while in other countries protection against imports is achieved by requiring regulation only on imported products.

In contrast, the Permacol surgical implant made from a cellular collagen matrix by Tissue Science Laboratories (Aldershot, UK) is provided in a variety of different configurations to suit different surgical applications, but does not include autologous tissue. As a result it has both FDA and CE mark approval for use in a variety of ways, including face and head surgery, urology/gynecology and general surgical procedures.

Similarly, Bioplant Hard Tissue Replacement (BHTR) from Bioplant (South Norwalk, Connecticut) is a non-resorbable copolymer that has been widely used as a bone substitute and is readily available throughout the U.S. and Europe.

Last October a Scientific Committee on Health and Consumer Protection at the European Commission defined eight recommendations on regulatory intervention at the EU level and the commission is currently working to produce a directive on minimum requirements. Regrettably, however, the proposed regulations will apparently still allow member states to impose additional requirements on autologous tissue-engineered products and will therefore not solve the present marketing and distribution problems.

Tumor therapy developments

Trumpf Medizin Systems (Umkirch, Germany) has launched in Europe its laser-induced interstitial thermotherapy system as a minimally invasive alternative to the standard surgical resection of benign or malignant tumors. Clinical applications currently include malignant tumors and liver metastases, but the method also has potential for use in treating tumors in the brain and breast tissue as well as nasopharyngeal tumors and benign tissue changes, according to the manufacturers. The procedure is monitored by MRI or ultrasound in real time and only a small percutaneous puncture access is required for catheter insertion with a micro-thin glass fiber inserted into the tumor site. High temperatures (60 to 100 degrees C) generated at the target denature protein molecules, causing irreversible damage to tumor cells.

A radically different tumor therapy approach is envisioned by researchers at Ark Therapeutics (London and Kuopio, Finland) who have published preclinical data successfully using their Scavidin technology in the treatment of malignant gliomas in animal models. Scavidin exploits a gene construct that combines the gene for macrophage scavenger receptor with the avidin gene. Administered via a suitable vector, it expresses a novel biotin-binding transmembrane receptor that migrates to the cell surface. This avidin-based receptor captures and internalizes biotinylated therapeutic compounds administered systemically, concentrating and releasing the drug specifically in the Scavidin-transfected cells.

"Our initial focus will be to develop the technology for targeting cytotoxic drugs and radiopharmaceuticals to solid tumors, said Ian Boyd, Ark's director of drug development.

"The Scavidin technology could be applied to any solid tumor, to target and concentrate the desired cytotoxic agents," said Professor Seppo Yla-Herttuala, Ark's consultant director of molecular medicine, who heads the research team at Kupio. "As a universal two-step approach, therapy would involve transfection of the tumor with the Scavidin construct to generate the high affinity biotin binding site on the expressed transmembrane receptor, followed by systemic administration of low concentrations of the required biotinylated cytotoxic drug."

P3-D vision for endoscopic procedures

Surgical Vision (Reading, England), in collaboration with Middlesex Hospital (London), has developed an improved 3-D vision system for use in endoscopy and the company says it is now actively pursuing commercialization of the system.

The equipment is based around autostereoscopic display technology and consists of a stereo-endoscope connected via a stereocamera and control unit to a 3-D display monitor. Autostereoscopic displays work on the same principle as stereoscopic displays, but need no special glasses.

A major problem for a surgeon conducting a minimally invasive surgical procedure using 2-D endoscopic vision and a conventional 2-D monitor is that important depth cues are missing from the image, making movement control very difficult. Successful development of the 3-D display monitor included an eye-tracking device to ensure that the surgeon was free to move in any direction without losing the full 3-D effect of the image.

The first fully working system has been in clinical use at Middlesex Hospital since early 1999. Evaluation showed that 2-D endoscopic vision impaired performance by 35% to 100% as compared to direct vision. 3-D vision reduced this handicap by 41% to 53%, with no side effects reported.

Mad cows and Creutzfeldt-Jakob disease

Maybe we have been too quick in assuming that people falling ill with new variant Creutzfeldt-Jakob disease (nvCJD) have contracted the disease by eating beef affected by bovine spongiform encepalopathy (BSE or mad cow disease). That is the thesis proposed by George Venters, a public health specialist, in the British Medical Journal.

His main argument is epidemiological: If the two diseases are related, the curve of new cases of nvCJD should copy closely that of BSE, with a buildup over several years. But the growth rate of new cases is too slow to correspond to an epidemic of food origin. Venters believes it is much more likely that nvCJD is an already existing form of the disease previously undetected, but today correctly diagnosed and registered by the epidemiological surveillance unit for CJD set up in Britain in 1990. Although Venters' hypotheses are not in themselves proof, they do place some doubts on the connection between BSE and nvCJD and the debate therefore remains open.