Injured spinal cord: Regeneration possible with epothilone

Damage to the spinal cord rarely heals because the injured nerve cells fail to regenerate. The regrowth of their long nerve fibers is hindered by scar tissue and molecular processes inside the nerves. An international team of researchers led by DZNE scientists in Bonn now reports in Science that help might be on the way from an unexpected quarter: in animal studies, the cancer drug epothilone reduced the formation of scar tissue in injuries to the spinal cord and stimulated growth in damaged nerve cells. Both promoted neuronal regeneration and improved the animals' motor skills.  

Nerve cells are wire-like conductors that transmit and receive signals in the form of electrical impulses. This function can be impaired by accidents or disease. Whether or not the affected nerves can recover largely depends on their location: for instance nerve cells in the limbs, torso and nose can regenerate to some degree and regain some or all of their function.

In contrast, the neurons in the brain and spinal cord do not have this ability. If they are damaged by accident or disease, the patient is likely to suffer long-term paralysis or other disabilities. But why is regeneration of these neurons and their long nerve fibers impeded? It is already known that inhibiting factors in newly formed scar tissue and other cellular processes block axon regrowth.

Figure: Cross section of Spinal Cord

Seeking the ideal treatment

"The ideal treatment for promoting axon regeneration after spinal cord injury would inhibit the formation of scar tissue," says Professor Frank Bradke, who leads a working group at the DZNE's site in Bonn and who conducted the study. "However, it is also important that the growth-inhibiting factors are neutralized while reactivating the poor axons' regenerative potential." A feasible administration of a potential treatment is also essential for clinical application.

In cooperation with international researchers, Bradke and his team have now managed to take another step towards the development of a future treatment. From their previous research, it was already known that stabilizing microtubules would reduce the formation of scar tissue and promote axonal growth. Microtubules are long, tubular filaments inside the cell that can grow and shrink dynamically. They are part of the cell's supportive skeleton, which also controls cell growth and movement.

The substance epothilone can stabilize microtubules and is already licensed on the American market -- as a cancer treatment. "It all depends on the dose," says Dr. Jörg Ruschel, the study's lead author. "In higher doses, epothilone inhibits the growth of cancer cells, while low doses have been shown to stimulate axonal growth in animals without the severe side-effects of cancer treatment." Epothilone is superior to other cancer drugs with a similar effect because it can penetrate the blood-brain barrier into the central nervous system, thus reaching the damaged axons directly.

One substance -- many effects

Experiments have shown epothilone works on several levels. Epothilone reduces the growth of scar tissue by inhibiting the formation of microtubules in the cells that form the scar tissue. Therefore they cannot migrate to the spinal cord lesion and cause wound scarring. At the same time, epothilone promotes growth and regeneration in the nerve cells by causing microtubules to grow into the damaged axon tips.

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Bioinformatics Department

Micromedic reports successful clinical study results for monitoring bladder cancer recurrence with the CellDetect non-invasive test

Micromedic Technologies Ltd., has announced the results of a blinded, multi-center clinical study using the Cell Detect non-invasive technology to detect bladder cancer recurrence in patients with a history of the disease. The Cell Detect test successfully identified cancerous cells in urine samples, with reported sensitivity of 84.4% and specificity of 82.7% for the study's primary endpoint. The blinded clinical study was conducted in nine medical centers, where urine samples from 217 subjects with a history of bladder cancer were tested. The study population included 121 healthy subjects and 96 patients currently suffering from the disease.

The results of the Cell Detect urine test were compared with results from biopsy or cystoscopy, in cases where biopsies were not performed. The results also indicated that the negative predictive value (NPV) was 98.5%. In addition to its high sensitivity for advanced stage tumors and high-grade malignancy, the test was also found to exhibit high sensitivity for early stage tumors and low-grade malignancies which are difficult to identify using other non-invasive tests currently available on the market.

The secondary endpoint showed that the sensitivity of other non-invasive comparator tests, urine cytology, BTA stat and NMP22 Bladder Check, was 50.0%, 68.8% and 17.4%, respectively. These findings indicate that the method is adequately sensitive for the purpose of accurate and early detection of the recurrence of the disease.

Following these successful study results, the company plans to secure a CE mark approval for a European launch of this non-invasive test later this year as well as to submit a Pre-IDE to the U.S. Food and Drug Administration (FDA).

"We are tremendously pleased with the results of the study that confirm the high performance of the CellDetect(R) urine test in accurately monitoring recurrence of bladder cancer," Steven Eitan, Micromedic's CEO, said. "By administering this test, millions of bladder cancer patients may be able to forego numerous costly and invasive tests, starting to receive treatment faster if their cancer is likely to recur. Following these successful results, we are also planning to conduct the required activities to quickly broaden the intended use to the early detection diagnostic market for additional millions of patients. The Cell Detect technology has the potential for diagnosing additional cancer indications."

The accuracy of this novel assay appears to be superior over any available non-invasive test, suggesting a potential to supplant some or all of the cystos copies required for bladder cancer surveillance. This is indeed great news for patients with history of bladder cancer, which may change their management."

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Biotechnology Department

How cells communicate

During embryonal development of vertebrates, signaling molecules inform each cell at which position it is located. In this way, the cell can develop its special structure and function. For the first time now, researchers of Karlsruhe Institute of Technology (KIT) have shown that these signaling molecules are transmitted in bundles via long filamentary cell projections. Studies of zebrafish of the scientists of the European Zebrafish Resource Center (EZRC) of KIT revealed how the transport of the signaling molecules influences signaling properties. 

Control of cell differentiation in the central nervous system.

Organisms, organs, and tissues are complex three-dimensional systems that consist of thousands of cells of various types. During embryonal development of vertebrates, each cell requires information on the position at which it is located in the tissue. This position information enables the cell to develop a certain cell type for later execution of the correct function. This information is transmitted via signal molecules, so-called morphogenes. These morphogenes are not homogenously distributed in the tissue, their concentration varies. Various concentrations activate various genes in the target cell.

The cells in the developing central nervous system receive their position information from signal molecules belonging to the family of Wnt proteins. The concentration of Wnt proteins determines whether a cell differentiates to a cell of the forebrain or of the afterbrain. "Smallest changes of the concentration or the transport direction may cause severe damage, such as massive malformations during embryonal development or formation of cancer."

For the first time now, the working group of Dr. Steffen Scholpp has shown that the Wnt proteins are transmitted specifically via long cell projections, so-called filopodia. In the Nature Communications journal, the scientists report that the signaling factors are loaded on the tips of the filopodia only. In this way, signaling can start immediately upon contacting. The signaling factors bind to the corresponding receptors of the target cell and induce the correct cell response.

 

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Biotechnology Department