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Source: Massachusetts General Hospital Summary: Physicians describe how their 13-year-old patient with alopecia totalis -- a total lack of scalp hair -- along with eczema, experienced significant hair regrowth while being treated with dupilumab.  Massachusetts General Hospital (MGH) physicians are reporting an unexpected side-effect from treatment with dupilumab, which is FDA approved for the treatment of moderate to severe eczema, also called atopic dermatitis. In their case report published in JAMA Dermatology, the physicians describe how their 13-year-old patient, who has alopecia totalis -- a total lack of scalp hair -- along with eczema, experienced significant hair regrowth while being treated with dupilumab, a drug marketed under the brand name Dupixent.
"We were quite surprised since this patient hadn't grown scalp hair since the age of 2, and other treatments that can help with hair loss did not in her case," says Maryanne Makredes Senna, MD, of the MGH Department of Dermatology, senior author of the JAMA Dermatology report. "As far as we know, this is the first report of hair regrowth with dupilumab in a patient with any degree of alopecia areata." In addition to longstanding alopecia, this patient had experienced extensive, treatment-resistant eczema since the age of 7 months. Treatment with prednisone and methotrexate, medications that can suppress the overactive immune system, led to limited improvement in the patient's eczema but no hair regrowth and was therefore discontinued. In July 2017 she began to be treated with weekly injections of dupilumab, which had recently received FDA approval. After six weeks of treatment, which led to significant improvement in eczema symptoms, she also noticed that fine light hairs called vellus hairs were appearing on her scalp. After seven months of dupilumab treatment, the patient had grown a significant amount of the pigmented hair that typically grows on the scalp. Because of a change in her insurance coverage, she had to discontinue dupilumab for a two-month period, during which she noticed shedding of the recently regrown hair. But after she could resume treatment in April 2018, the hair growth resumed and has continued. Senna explains that dupilumab's mechanism of targeting a key immune system pathway known to be overactive in eczema could explain its action against alopecia, since recent studies have suggested other elements of the same pathway may induce autoimmune hair loss. "Right now, it's hard to know whether dupilumab could induce hair growth in other alopecia patients, but I suspect it may be helpful in patients with extensive active eczema and active alopecia areata," she says. "We've submitted a proposal for a clinical trial using dupilumab in this patient population and hope to be able to investigate it further in the near future." Senna is the principal investigator of the Hair Academic Innovative Research (HAIR) clinical research unit at MGH and an instructor in Dermatology at Harvard Medical School. Source: University of Bonn Summary: Hypotrichosis simplex leads to progressive hair loss starting in childhood. Geneticists have now deciphered a new gene that is responsible for this rare form of hair loss. Changes in the LSS gene lead to impairment of an important enzyme that has a crucial function in cholesterol metabolism.  Hypotrichosis simplex leads to progressive hair loss starting in childhood. A team of researchers led by human geneticists at the University Hospital of Bonn has now deciphered a new gene that is responsible for this rare form of hair loss. Changes in the LSS gene lead to impairment of an important enzyme that has a crucial function in cholesterol metabolism. The scientists now present their findings in the journal the American Journal of Human Genetics.
In infancy, fine hair tends to sprout sparsely. With increasing age, hair loss progresses. Ultimately, only a few hairs are left on the head and body. Hypotrichosis simplex is a rare form of hair loss (alopecia). The condition is limited to a few hundred families worldwide. So far, only a few genes are known that are causally related to the disease. Under the leadership of the Institute of Human Genetics at the University Hospital of Bonn, a team of researchers from Germany and Switzerland has now deciphered mutations in another gene that are responsible for hair loss. The scientists examined the coding genes of three families that are not related to each other and are of different ancestry. A total of eight relatives showed the typical symptoms of hair loss. All those affected had mutations in the LSS gene. "This gene encodes lanosterol synthase -- LSS for short," said Prof. Dr. Regina C. Betz from the Institute of Human Genetics at the University Hospital of Bonn. "The enzyme plays a key role in cholesterol metabolism." However, the cholesterol blood values of those affected are not changed. Betz: "There is an alternative metabolic pathway for cholesterol, which plays an important role in the hair follicle and is not related to blood cholesterol levels." Mutation leads to displacement of lanosterol synthase Using tissue samples, the scientists tried to find out exactly where the lanosterol synthase is located in the hair follicle cells. The hair roots are formed in the follicle. If the LSS gene is not mutated, the associated enzyme is located in a system of very fine channels in the follicle cells, the endoplasmic reticulum. If a mutation is present, the lanosterol synthase also spreads outside these channels into the adjacent substance, the cytosol. "We are not yet able to say why the hair is falling out," says lead author Maria-Teresa Romano, a doctoral student in Prof. Betz's team. "It is likely that the displacement of LSS from the endoplasmic reticulum results in a malfunction." Prof. Dr. Matthias Geyer from the Department of Structural Immunology at the University of Bonn investigated the consequences of mutations for the structure of the enzyme lanosterol synthase. With him and Prof. Betz, there are now two principal investigators from the Cluster of Excellence ImmunoSensation of the University of Bonn, which was impressively endorsed in the latest round of the Excellence Competition and will receive further funding. Improved diagnosis For the scientists, the current study result is an important finding: Each further gene decoded is yet another part of the jigsaw and helps to complete the picture of the biological basis of the disease. "A better understanding of the causes of the disease may in future enable new approaches to the treatment of hair loss," said the human geneticist. But there is still a long way to go. However, the discovery of the gene already contributes to an improved diagnosis of the rare disease. Betz: "Those affected by hypotrichosis simplex only have to deal with hair loss. This is upsetting, but other organs are not affected." Source: University of Alabama at Birmingham Summary: Researchers have reversed wrinkled skin and hair loss, hallmarks of aging, in a mouse model. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.  Wrinkled skin and hair loss are hallmarks of aging. What if they could be reversed?
Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age. "To our knowledge, this observation is unprecedented," said Singh, a professor of genetics in the UAB School of Medicine. Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive. In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer. "This mouse model," Singh said, "should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role." The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive. In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males. Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA. Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues. The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging -- intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking. Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging. The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor -- a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling. The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation. Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls "surprising." "It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype," Singh said, who has a secondary UAB appointment as professor of pathology. "Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA." |
AuthorBy Masaakii Archives
May 2024
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