New perspectives on the treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the presence of painful nodules, abscesses, chronically draining fistulas, and scarring in apocrine gland-bearing areas of the body. The exact pathogenesis of HS is not yet well understood, but there is a consensus in considering HS a multifactorial disease with a genetic predisposition, an inflammatory dysregulation, and an influence of environmental modifying factors. Therapeutic approach of HS is challenging due to the wide clinical manifestations of the disease and the complex pathogenesis. This review describes evidence for effectiveness of current and emerging HS therapies. Topical therapy, systemic treatments, biological agents, surgery, and light therapy have been used for HS with variable results. Adalimumab is the only US Food and Drug Administration (FDA) approved biologic agent for moderate-to-severe HS, but new therapeutic options are being studied, targeting different specific cytokines involved in HS pathogenesis. Comparing treatment outcomes between therapies is difficult due to the lack of randomized controlled trials. Treatment strategy should be selected in concordance to disease severity and requires combination of treatments in most cases

Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.Nation Foundation and by grants from the Spanish Ministry of Economy and Competitivity (SAF-2014-57539-R and SAF2017-87698-R) to M.D.L. and from NIH-NINDS (R01NS073940) to K.S.B. A.P.-C. was a recipient of the FPU predoctoral fellowship from the Spanish Ministry of Economy and Competitivity and Fundación Ramón Areces to the Centro Biología Molecular Severo Ochoa

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Even though the idea that amyloid β peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of β-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between β-amyloid and tau alterations may take place in vivo.This project was funded in part by EC grant DIADEM QRLT-2000-026362, SAF2004-07802 and UTE project CIM

Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP

Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65years) Alzheimer’s disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early onset AD (mean age at onset of 52.9 years; range 31– 64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d’Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new nonsynonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations

Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders. © 2019 The Authors.This work was supported by Wylder Nation Foundation and by grants from Spanish Ministry of Economy and Competitivity (SAF-2014-57539-R and SAF2017-87698-R) to M.D.L. and from NIH-NINDS (R01NS073940) to K.S.B. A.P-C was a recipient of the FPU pre-doctoral fellowship from the Spanish Ministry of Economy and Competitivity. L.S. was a recipient of the Edward H. Schuchman Research Fellowship from the National Niemann-Pick Disease Foundation. E.H.S. and X.H. were supported by a MERIT award from the NIH (R37 HD28607) to E.H.S.Peer reviewe