Arthritis affects around 10 million people in France alone, and World Health Organization (WHO; Geneva, Switzerland) estimates place arthritis at the top of the global list of afflictions causing physical handicaps. Advances in better understanding the mechanisms of arthritis and in the development of new and more effective treatments have given rise to hopes that the causes of arthritis can be treated and that new therapies will become available by 2010. As a result, WHO has decided to call the first decade of this millennium "the bone and joint decade."
The new treatments that are envisioned will not simply be palliative like the anti-inflammatories that reduce the pain and slow temporarily evolution of the disease. The therapies now appearing will attack directly the cause of the problem, the destruction of bone cartilage. "Advances in research are making us very optimistic about therapeutic possibilities. Five to 10 years seems to me reasonable for the arrival of the first treatments," estimated Professor Francis Berenbaum, head of the rheumatology department at H pital Saint-Antoine (Paris) and leader of a research group at the Universit Pierre et Marie Curie (also Paris). He said the priorities are to develop diagnostics to detect arthritis at an earlier stage, to reduce the rate of destruction of cartilage and to repair damaged cartilage.
The new developments are the result of a radically different way of viewing arthritis. Over the past 15 years, each world rheumatology congress, including the latest last November in San Francisco, California, has seen new discoveries that have made necessary a rethinking of rheumatology manuals. It was generally thought that arthritis was not an inflammatory disease, but due to mechanical wear of the cartilage. More recently it has been proposed that the problem is not mechanical wear, but that destruction of cartilage is of biochemical origin, with a major inflammatory component. Now it is suggested that erosion of the cartilage is slow and continuous; it seems probable that the process develops in stages.
"These latest theories are not yet widely understood, not only by the general public, but equally by otherwise well-informed sectors," Berenbaum said. He noted that understanding arthritis depends on a deeper understanding of cartilage, a living tissue composed of a matrix formed of collagen and proteoglycans, and chondrocyte cells, which secrete the matrix and which are continuously renewed. In normal people, formation and degradation of cartilage is in equilibrium, whereas in arthritic patients a disequilibrium results in cartilage degradation. It is not yet clear, however, how normal cartilage starts to autodestruct.
"One hypothesis is that mechanical receptors, the integrins, present on the surface of chondrocyte cells, are stimulated by high pressures during articulation. Under the effect of the message received, chondrocytes produce collagen and proteoglycans of inferior quality, and increase synthesis of proteases to degrade them," said Professor Xavier Chevalier, chief of rheumatology services at the H pital Henri-Mondor (Paris).
Pharmaceutical research is exploring two main avenues: on one side, cutting communication between integrins and the nucleus of the chondrocytes so as to suppress the signal to synthesize the destructive proteases; alternatively, to block directly the synthesis of these enzymes in the cell nucleus. Clearly it may well be several years before an effective therapeutic is available, but the first drug company to develop such a product could have a veritable blockbuster.
A third way is to aim at inhibiting the inflammatory process, the target being to aim at reducing the pain and slowing the cartilage destruction process. Much current research is concentrating on developing anti-inflammatories capable of inhibiting cytokines and particularly one of the most important, interleukin 1 (IL1), which can also cause the chondrocyte nucleus to produce destructive proteases. A number of pharmaceutical companies are working in this area.
In parallel with these lines of development in treating arthritis are projects aimed at repairing damaged cartilage. The injection of normal autologous chondrocytes harvested from the patient, grown in vitro and re-injected, which was first developed in 1994 by Mats Brittberg at the University of Gottenborg (Gottenborg, Sweden), is widely used in Europe. Two developments of this technique have been proposed. Dr. Farshid Guilak of Duke University (Durham, North Carolina) has produced in vitro chondrocytes grown from autologous fat cells of the patient. This approach is expected to be available in about three years. In a similar approach, Chevalier and Dr. Mait Corval, research director of the Inserm unit 530 at the University of Paris, have isolated from the patient's bone marrow chondrocyte precursor cells (the famous adult stem cells) to be grown in vitro before transplanting back into the patient. Alternatively, it may be possible to stimulate cartilage formulation by injecting growth factors in situ.
OrthoLogic (Tempe, Arizona) has a license from Chrysalis Biotechnology (Galveston, Texas) for Chrysalin, a 23-amino acid peptide which OrthoLogic believes could be delivered arthroscopically for a variety of soft tissue indications, including articular cartilage repair. Preclinical animal studies at the University of Texas in Galveston and North Shore University Hospital (Manhasset, New York) have shown accelerated repair compared to controls. "These were two independent studies that yielded the same result — this product is very potent. The repair of articular cartilage seen with Chrysalin shows tremendous promise for human articular cartilage repair," said Jim Ryaby, vice president of research at OrthoLogic.
All these therapies, however, are aimed at treating patients at a relatively advanced stage of arthritis. Chevalier has emphasized that medical imaging, which already can provide 3-D images of articulation, will become increasingly important. For the future, he envisions 3-D imaging to identify at an early stage small anomalies in cartilage, well in advance of the appearance of any pain. At that stage, it will be possible to take precautionary measures to slow down or to avoid the onset of arthritis completely.
Dolly's arthritis raises worries over cloning
PPL Therapeutics (Roslin, Scotland) has confirmed that the world's most famous clone, Dolly the sheep, has for several months been suffering from arthritis in a hip joint, an atypical location for the onset of arthritis in sheep. The announcement has caused concern that the cloning process used may be producing animals which age unnaturally early or which are susceptible to an usually high rate of age-related diseases.
Dolly was the first mammal to have been cloned from an adult cell using nuclear-transfer technology, and has herself produced six healthy lambs in normal breeding programs. The cell from which she was cloned was taken from a six-year-old ewe, and PPL has said that when born, the telomeres at the end of Dolly's chromosomes were shorter than would be expected for a young animal, suggesting that her cells were perhaps essentially "older" than they should have been. Alan Colman, research director at PPL, stressed, however, that it was not possible to say whether the arthritis is linked to the cloning technology or only a natural development. "We will simply never know in Dolly's case. We can now only speculate about whether one cloned sheep with an arthritic hip means that other healthy cloned animals will generally be more prone to the early onset of age-related or other diseases or, indeed, whether they will have shorter life spans."
The possibility of premature aging has inevitably resulted in speculation as to whether organs or tissues from cloned animals might age more rapidly when used in human transplantation. Colman pointed out that the scientific reality is that cloned animals would not be used directly as organ donors. Final organ-donor animals would not be clones themselves, he said, but would be bred normally from a carefully monitored stock of non-immunogenic animals.
Morphometric MRI in Alzheimer's diagnosis
Since 1990, magnetic resonance imaging has made possible substantial advances in the volumetric studies of the smaller structures of the brain. In particular, assessment of the atrophy of the hippocampus can provide an early indication of onset of Alzheimer's disease, with a reduction in volume of 20% to 40%.
"The contribution of MRI (to early diagnosis) is much more important than studies indicate because the greater the reduction in the volume of the hippocampus in a patient with memory problems, the greater the risk of the patient developing full-blown Alzheimer's," said Stephane Leh ricy of the neuroradiology department at the Hopital de la Salpetri re (Paris). "In addition, amnesiac problems associated with Alzheimer's disease correlate with reduced hippocampus volumes although the converse is not true." The routine use of morphometric MRI examinations will depend on the availability of new software to facilitate interpretation, and are currently under development, Leh ricy said.
MRI can potentially be used to evaluate brain function, so that so-called functional imaging permits the visualization of reductions in brain blood supply (perfusion MRI), increases in the diffusion of water molecules (diffusion MRI), reductions in other molecules such as N-acetylaspartate (spectroscopy) or the level of brain activity relative to tasks undertaken — all valuable indicators in the evolution of Alzheimer's disease, according to Leh ricy.
Currently only one case in two of Alzheimer's disease in France is formally diagnosed. Of 550,000 cases of dementia, an estimated 350,000 are Alzheimer's, with 100,000 new cases each year. Two-thirds of these are over 79 years of age. With the general aging of the French population, these figures are projected to double by 2020.
Strakan majors in nitric oxide therapy
Strakan (Galasheils, Scotland) is developing topical nitric oxide (NO) gas as a novel antimicrobial therapy. The program is based on research at the University of Aberdeen (Aberdeen, Scotland) by Nigel Benjamin and Anthony Omerod which showed that NO is part of the natural host-defense system of the human body. "We excrete nitrate through the skin, which is reduced to nitrite by bacteria. This reacts with organic acids in perspiration, producing NO which has an antimicrobial action on skin," said Harry Stratford, Strakan's CEO. "We've developed a cream with an organic acid and nitrite. Once these are mixed, NO gas is given off immediately."
Topical NO therapy is initially being used in viral infections such as anogenital warts, hand and foot warts and molluscum contagiosum, a poxvirus infection affecting children, especially in Japan. Stratford said the therapy also has potential in bacterial skin infections and in fungal infections such as athlete's foot.
In a double-blind randomized trial of topical NO in molluscum contagiosum, for which there is currently no other treatment, the cure rate for those on therapy was 75%, compared to 21% in the control group. Phase I trials are ongoing and pan-European Phase II trials are planned for Britain, Germany, the Netherlands and Sweden.
Nitric oxide release in new therapies
NicOx (Sophia Antipolis, France) creates patentable new therapeutics by grafting a nitric oxide-releasing moiety onto existing drugs with well-known pharmacologic properties. As a result, the company benefits from a broad base of knowledge from which to design preclinical and clinical development studies. The company had six NO-related compounds in human clinical testing, including three in Phase II, last year.
But 2002 could be a pivotal year for NicOx as a number of Phase II trials are completed and other products enter clinical trials. "The year 2002 will be critical and we expect the release of Phase II data to be an important step in our evolution and provide a good stage for increased partnering," said Elizabeth Robinson, executive vice president of corporate development at NicOx. "We are talking to everyone and, in particular, looking for partners for further clinical development of compounds and licensing agreements."
The company has an existing agreement with AstraZeneca (London) to develop and commercialize NO-NSAIDS for treating pain and inflammation. AstraZeneca has Phase II trials under way for a NO-releasing derivative of the NSAID naproxen. NicOx also has recently signed a research collaboration agreement with Biolipox (Stockholm, Sweden) for a novel class of nitric oxide-releasing respiratory therapeutics.
Separately, NicOx has reported positive Phase I trial results on NCX 701, a nitric oxide-releasing derivative of paracetamol, in development to treat pain and fever. The company also has received a second grant from the National Cancer Institute (NCI; Frederick, Maryland) for research into its nitric oxide-releasing aspirin compounds and to study their effect on colon cancer.
Siemens to build Egyptian drug unit
Siemens' Industrial Solutions and Services unit (Erlangen, Germany) has won an $11 million contract from Hebi Health Care (Stockholm, Sweden) to build a new greenfield pharmaceutical plant in Qift, Egypt. The plant, which will annually produce 200 tons of antibiotic precursor 7-amino cephalospirinic acid (7-ACA), will be completed this summer. Heba Health Care produces pharmaceuticals, fine chemicals and hygiene products and already has three production plants in Egypt.
Separately, Siemens has said it is in talks with several potential buyers of an unusual non-core asset: a 49% stake in Krauss-Maffei Wegmann (KMW; Kassel, Germany), which builds Germany's main battle tanks and other land-based defense systems.
"We want to sell it and get the cash flow out, the earlier the better. There is no pressure, but we hope that we will no longer be the owner of this business by the end of 2002," said Heinrich von Pierer, Siemens' chief executive. Siemens acquired the KMW stake in 2000 when it acquired some of the engineering interests of Mannesmann (Dortmund, Germany), which was acquired by Vodafone of the United Kingdom. KMW's sales last year were around $625 million.
TNS projects above-average growth in 2002
Taylor Nelson Sofres (TNS; London) currently the world's fourth-largest market research company, expects to outstrip market growth in the 2001/2002 financial year ending this month, despite the effects of Sept. 11 and the economic crisis in Argentina. Strong growth in the health care division has helped offset a fall in information technology and telecom-related business in the second half.
David Lowden, finance director, said, "Our health care division has benefited from an increase in demand for services from pharmaceutical companies. We have also benefited from investments in the sales force and from new methods of monitoring drugs people are taking."
However, TNS added that margins had been squeezed as a result of the terrorist attacks and were likely to be closer to 0.3% than the anticipated 0.5%. The company said revenues had increased in all regions, with Europe reporting an underlying improvement ahead of the market.
Peptide protector for Type 1 diabetes
Peptor (Rehovot, Israel) has announced that its experimental peptide DiaPep 277 has halted the progression of early Type 1 diabetes during Phase II trials. Researchers at Peptor and the Weizmann Institute (also Rehovot) have identified an immunomodulatory component of the 60KDa heat-shock protein (hsp60) expressed by insulin producing beta cells of the pancreas. The component, called p277, returned the beta-cell function in mice genetically predisposed to Type 1 diabetes by shifting the immune response profile from a pro-inflammatory to an anti-inflammatory response.
Peptor has now shown that the same peptide retards progression of diabetes in humans. Only three injections of DiaPep277 over a period of six months prevented a fall in C-peptide levels, a clinical marker of progression of diabetes.