New Alzheimer's Disease Model Offers Hope for a New Array of Therapeutic Targets

Biomedical research is learning a great deal about how the brain works at the cellular level. Alzheimer's Disease, for example, is being seen more as an imbalance within normal cell processes -- like cancer. A better understanding of these processes should allow more precise targeting of drug research.

One of the mysteries of AD has been the normal function of the amyloid precursor protein (APP) which are concentrated at the points where neurons connect. Even though the sticky amyloid plaques which have been viewed as a hallmark sign of AD result from APP, it seems unlikely that APP exists simply to cause Alzheimer's disease. In their study, scientists from the Buck Institute and the CNRS (Centre Nationale de la Recherche Scientifique) show that APP binds to netrin-1, a protein that helps to guide nerves and their connections in the brain, as well as helping nerve cells to survive. When netrin-1 was given to mice that have a gene for Alzheimer's disease their symptoms were reversed, and the sticky amyloid was reduced. These results suggest that the long-held belief that AD is caused by brain cell damage inflicted by the amyloid plaques may be wrong; instead, it is beginning to appear that the disease stems from an imbalance between the normal making and breaking of connections in the brain, with netrin-1 supporting the connections and the amyloid breaking the connections -- both by binding to APP and activating normal cell programs. Not only did the netrin-1 binding to APP keep the nerve cells alive and connected, but it also shut down the production of the amyloid, all of which makes it an interesting potential therapeutic. _Scientistlive

In the past few decades, the therapeutic viewpoint toward Alzheimer's has paced the rapidly growing knowledge of the underlying mechanisms of the disease. Already we have gone through multiple generations of treatments, with several radically new treatments in the pipeline. If "netrin-1" or its analogues can be delivered to the proper brain regions, and can at least partially reverse both the histological and the clinical pathology in AD, we will not only have a better treatment, but we will have one more promising lead to follow.

New Stem Cell Hope For Parkinson's

Researchers in Bonn have developed a method of culturing an indefinite supply of replacement neural stem cells -- including the cells that fail in Parkinson's -- from a single embryonic source.

"The new cells, in contrast, serve as an inexhaustible source: they provide a supply of human neural cells over periods of months and years without demanding any recourse to supplementary embryonic stem cells", declares Professor Dr. Oliver Brüstle, head of the research team at the Institute for Reconstructive Neurobiology at Bonn University.

Using animal experiments, the researchers in Bonn provided direct proof that these artificially derived neural cells will also function. Transplanted into the brain of a mouse, these cells made contact with the recipient brain and were subsequently able both to send and receive signals. "This is the first direct evidence that neural cells derived from human stem cells are capable of synaptic integration in the brain", declares Dr. Philipp Koch, the original author of the study. The scientists in Bonn are now also hoping to exploit this inexhaustible cell source to study neurodegenerative diseases and possible active agents directly in human neural cells. _MNT

If scientists can prevent the rejection of donor stem cells, the pathway toward routine replacement of aging brain tissue is now being constructed. Adult induced pluripotent stem cells from the patient herself is the best means for preventing rejection of tissue and stem cell implants. But if embryonic cell and tissue banks are able to carry a large "on-demand" supply of suitable cells, they will be quite useful.

Clearly the promise of stem cell research applies to other diseases besides Parkinson's, and to other organs besides the brain.

The problem for the US -- where funding for the development of new embryonic stem cell lines is expected to be expanded -- is the overall economy. The new government appears not to understand how a market economy recovers from a recession -- a recession that was brought on by bad government policies to begin with. A helpful hint to Obama and Pelosi: get rid of those bad government policies! (CRA etc)

Interferon Makes Dormant Cells Vulnerable

Dormancy is an important protection mechanism of stem cells. First, it protects their genetic material from genetic alterations, which happen primarily during cell division. In addition, dormancy helps them escape attacks of many cytotoxins, which act only on dividing cells. _MNT

Many cancer stem cells are likewise dormant, which can protect them from chemotherapy. Waking these cancer stem cells up before chemotherapy is one way to kill more of them, and increasing chances for a remission. Interferon seems to wake stem cells up from a dormant state, and force them to divide. This makes them vulnerable to mutation and to cytotoxins.

Patients suffering from a type of blood cancer called chronic myelogenous leukemia who are treated with a drug called Gleevec almost always relapse after drug treatment has ended. Several patients were given interferon-alpha prior to the Gleevec treatment. Surprisingly, these patients experienced long relapse-free phases without any medication. "We believe that the leukemia stem cells were awakened by the interferon administration and, thus, were sensitized to elimination by Gleevec," Andreas Trumpp explains. _MNT

The other side of the story is that interferon makes normal stem cells vulnerable to cytotoxic agents, so that blood forming stem cells in the bone marrow will be killed by some chemotherapeutic agents such as 5-FU, if interferon is given first. This can cause severe anemia and death.

This knowledge can lead one to speculate about the effects of viral infections and natural interferon on stem cells in other locations, such as the brain. The constant infectious assault experienced in the tropics, for example, may lead to chronic depletion of stem cells with all of the failure of normal regeneration that such depletion implies.

Each scientific discovery becomes the trigger for new exploration. The contemporary human mind cannot keep up with the multiple ongoing chain reactions of knowledge, but computers should be of some help.

Skin Cells Programmed to Become Heart Cells

Using techniques of induced pluripotent stem cell conversion, scientists at the University of Wisconsin created heart cells out of skin cells. The idea is to take a person with heart failure, make functioning replacement heart cells from abundant skin cells, and give the person what is in essence a new heart.

"This is the first demonstration that human induced cells can form different types of heart cells in a dish," said study co-author Tim Kamp, a University of Wisconsin cell biologist.

The latest findings, published Thursday in Circulation Research, suggests that failing hearts might be mended.

"We didn't know whether they could form heart cells efficiently," said Kamp. "But they successfully formed heart cells with all the electrical and organizational properties we'd expect."

In the last few years, induced pluripotency has been hailed as an uncontroversial alternative to embryonic stem cells, production of which requires the destruction of embryos.

Reprogramming flakes of skin would be a far easier alternative. _Wired

Novel Alzheimer's Drugs Coming

• As many as 5.2 million people in the United States are living with Alzheimer’s.

• 10 million baby boomers will develop Alzheimer's in their lifetime.

• Every 71 seconds, someone develops Alzheimer’s.

• Alzheimer's is the sixth-leading cause of death.

• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $148 billion each year. _Alz

The older you get, the more likely that you will suffer some form of cognitive impairment -- most likely Alzheimer's. With the aging of North America and the developed world, the need for better ways to diagnose and treat Alzheimer's is critical.

New cognitive tests are being developed to determine whether a person with early cognitive impairment can drive safely. Special MRI techniques can show the early tell-tale signs of Alzheimer brain atrophy.

On the treatment side, "brain games" that develop short term memory appear helpful in reversing early cognitive impairment.

Another hopeful bit of news is that Rember and Dimebon -- two novel drug treatments for Alzheimer's -- are working their way through human drug trials, and show some promise.

A bit further in the future is the promise of Ampakines. Cortex Pharmaceuticals is the foremost developers of Ampakines for a wide range of disorders -- including Alzheimer's in the long run.

Further into the future, an even wider array of drugs are being developed to target several pathological mechanisms that are believed to contribute to Alzheimer's.

The main question at this time appears to involve financing for drug discovery and testing in the midst of an international financial crisis. US governmental policies under the new administration suggest that US pharmaceutical research and research into other vital innovative technologies will be short-changed. New drug development may well move offshore from the US to East and South Asia, where capital is less likely to be diverted to non-productive ends.

It is ironic that just when a relaxation of stem cell research regulations occurs, that draconian economic re-structuring should threaten the future of technological development in the biosciences and most other high tech fields.

Genetically Modified Regenerative Skin Graft Material Designed to Resist Infection

Stratatech’s StrataGraft® tissue is a second-generation human skin substitute that exhibits normal human skin structure and function. It is manufactured using the company’s proprietary NIKS® human keratinocytes, which were discovered at the University of Wisconsin. Keratinocytes are the cells that make up approximately 90 percent of the epidermis, the outer layer of human skin. NIKS® cells are a consistent source of pathogen-free, non-tumor-producing, long-lived adult progenitor cells. These cells faithfully reproduce normal human skin tissue architecture and barrier function when cultured appropriately. _StratatechCorp.

Regenerative medicine company Stratatech Corporation has developed a genetically tweaked living skin substitute for use in skin grafting. The genetic modifications of the living skin replacement makes it far more resistant to infection than currently available skin graft materials -- including autologous skin grafts.

The anti-infective capacity of Stratatech’s genetically-engineered tissue, which is being developed and commercialized by the company as ExpressGraft™ Enhance skin substitute through a worldwide exclusive license from the Wisconsin Alumni Research Foundation, or WARF, is produced by genetically engineering the elevated expression of a naturally-occurring antimicrobial host defense peptide called hCAP-18/LL-37. hCAP-18/LL-37 was selected because of its broad antimicrobial activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant E. faecalis (VRE) and other antibiotic-resistant hospital-acquired infections, as well as some fungi and viruses. The enhanced tissue possesses a full-thickness structure and barrier function similar to that of native human skin. The cell type used to generate the ExpressGraft™ tissue has been demonstrated to be non-tumor-producing and free from detectable pathogens, characteristics critical for cell-based, regenerative medicine therapies for patient use.

“Bacterial infection is a substantial cause of skin graft rejection and additional health care costs,” said Lynn Allen-Hoffmann, Ph.D., Stratatech’s founder, chief scientific officer and chief executive. “The potent anti-infective capability Stratatech has engineered in our living human skin substitute can be an important tool in improving skin-injury patient outcomes, and reducing the incidence and expense of hospital-acquired infections. We look forward to beginning the clinical evaluation of our antimicrobial skin substitute in the near term.

...Stratatech’s genetically-engineered skin substitute was generated using a non-viral vector, or carrier. The company believes it is the first time a virus-free approach has been used to genetically modify a living, cell-based tissue substitute. The data published in Molecular Therapy demonstrate that the modified tissue contained 139-fold more anti-infective proteins called host defense peptides than unmodified tissue in vitro. _BusinessWire

This is only the beginning of genetically improved, artificially grown bio-replacement materials. This skin replacement product from Stratatech should do well in the marketplace if it lives up to its promotion. But expect competing products that improve on the ExpressGraft's performance to emerge before long. This graft material does not perfectly reproduce the full, intricate layered structure of natural skin. But it is a good start.

Other more intricately structured grown replacement parts should follow on rather quickly. We are entering the age of regenerative medicine, when body parts and tissues will be grown in labs, rather than being donated by accident and crime victims. If these replacements can be designed to be tougher than the original parts being replaced, all the better.