Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
There is no treatment for systemic amyloidosis, which is responsible for one in a thousand deaths in developed countries. In the U.S., it kills 5,000 people a year. Amyloid is a group of chemically diverse proteinaceous fibrils that bunch as pathological deposits outside cells in amyloidosis diseases. The protean depredations of systemic amyloidosis extend to attacks on major organs and tissues of the body. In the pancreas, they cause Type II diabetes and its complications; in the kidney, patients on dialysis succumb.
The best known of these ubiquitous disorders of protein misfolding are the amyloid-beta senile plaques that are the hallmark of Alzheimer's disease (AD). The jury is still out as to whether these insoluble fibrils that wrap around neurons in the AD brain are the cause or effect of the disease.
A small-molecule protein called serum amyloid P component (SAP) universally infests amyloid deposits - notably AD's amyloid-beta plaques. SAP binds fibrils and makes them recalcitrant to breakdown by the body. Now there is a palindromic compound named CPHPC, which prevents SAP from binding. It blocks SAP's attachment site and hastens its degradation by the liver.
CPHPC is about to undergo clinical trials of safety and efficacy in five Alzheimer's patients. Its preclinical studies in mice are reported in Nature dated May 16, 2002, under the title: "Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis." Its principal authors are at the University College Medical School in London and F. Hoffmann-La Roche Ltd. in Basel, Switzerland.
They report, "Continuous infusion of CPHPC for five days accelerated whole-body clearance of radiolabeled human SAP tracer, with which the amyloid deposits had previously been loaded, and removed all the endogenous mouse SAP from the deposits. Injection of just 100 micrograms of CPHPC into mice transgenic for human SAP reduced circulating human SAP values by greater than 95 percent within three hours," but not in wild-type animals.
In seven human patients with systemic amyloidosis, intravenous infusion of CPHPC for 48 hours produced "rapid and consistent depletion of circulating SAP in all subjects . . . and remained low for prolonged periods of time." A subsequent trial was held on 19 such patients - aged 43 to 67 - who received daily CPHPC infusions or injections for up to 9.5 months. Plasma SAP levels went down to a mean 5 percent of pretreatment levels. "Although many of these patients," the Nature paper observed, "had end-stage disease, and were offered CPHPC because they had either already failed to respond to all other possible treatments, or no other treatment exists for their type of amyloidosis, most of them remained clinically stable throughout treatment."
Stress Hormone In Human Skin Gland Influences Psychiatric As Well As Dermatological Problems
The link between stress and skin-related problems - such as oiliness (seborrhea), acne and baldness - is not all in your head. It's in your oil glands, too.
A paper in the Proceedings of the National Academy of Sciences (PNAS), dated May 14, 2002, tells why and how. Its title: "Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes." Among its authors are research dermatologists at the Free University of Berlin.
They report that a stress hormone called corticotropin-releasing hormone (CRH) resides in and acts on the sebaceous gland. This skin gland is found around hair follicles that secrete skin oil. They detected CRH and associated receptors and binding proteins in cultured cells from human sebaceous glands. The hormone caused these cells to increase their output of lipids or oil, suggesting a possible role for CRH in skin disorders such as acne and seborrhea. Moreover, testosterone, the male sex hormone, as well as human growth hormone, each altered CRH receptors - perhaps indicating a role for CRH in male pattern baldness.
But that's not all. CRH, they found, regulates physiological and behavioral responses to stress. Some scientists suggest that psychiatric disorders such as depression and anxiety might be caused by dysfunction in the CRH system.
The PNAS paper leads off with this speculative rationale: "Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal [HPA] axis. Such a pathway . . . may occur in human skin, and lately in the sebaceous glands, because they express neuropeptide receptors. Corticotropin-releasing hormone is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress."
Scripps, Novartis Announce First Gene Expressing Heat-Sensitive Molecular Thermometer' Protein
By coincidence, Science for May 17, 2002, released online May 16, carries a paper that also deals with skin-cell sensitivity. Its title: "A novel heat-sensitive TRP channel expressed in kertatinocytes [the major type of skin cell]." Its authors are at the Scripps Research Institute in La Jolla, Calif., jointly with the Genomics Institute of the Novartis Research Foundation. They report having identified and cloned the first gene known to make skin cells able to sense warmth and heat.
Their gene makes a protein that is a type of transient receptor potential (TRP) channel. That membrane aperture opens when it registers a specific temperature, allowing ions to pass through and generate an electrical potential that signals the brain. The authors surmise that gene product might be an important target for analgesic drugs, because like other TRP channels it may be involved in inflammation and pain mediation. They note that the TRP channel is the first temperature-sensing molecule identified that becomes activated at warm and hot temperatures - 33 degrees Celsius (91.5 F).