No abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord progressively leading to paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms. The clinical manifestations observed in ALS appear relatively late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult. Therefore, novel strategies for early diagnosis of neurodegeneration, to monitor disease progression and to assess response to existing and future treatments are urgently needed. Factually, many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient's own cells. The ALS-TES presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions. Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS skin model could represent a renewable source of human tissue, quickly and easily accessible to better understand the physiopathological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.

Patients with peripheral nerve injuries face unpredictable and often suboptimal functional outcome, even following standard microsurgical nerve repair. The challenge of improving such outcomes following nerve surgical procedures has interested many research teams, in both clinical and fundamental fields. Some innovative treatments are presently being applied to a widening range of patients, whereas others will require further development before translation to human subjects. This article presents several recent advances in emerging therapies at various stages of clinical application. Nerve transfers have been successfully used in clinical settings, but new indications are being described, enlarging the range of patients who might benefit from them. Brief direct nerve electrical stimulation has been shown to improve nerve regeneration and outcome in animal models and in a small cohort of patients. Further clinical trials are warranted to prove the efficacy of this exciting and easily applicable approach. Animal studies also suggest a tremendous potential for stem and precursor cell therapy. Further studies will lead to a better understanding of their mechanisms of action in nerve repair and potential applications for human patients.