Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2.
Esophageal achalasia is a primary motility disorder characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis. Achalasia is a chronic disease that causes progressive irreversible loss of esophageal motor function. The recent development of high-resolution manometry has facilitated the diagnosis of achalasia, and determining the achalasia subtypes based on high-resolution manometry can be important when deciding on treatment methods. Peroral endoscopic myotomy is less invasive than surgery with comparable efficacy. The present guidelines (the "2019 Seoul Consensus on Esophageal Achalasia Guidelines") were developed based on evidence-based medicine; the Asian Neurogastroenterology and Motility Association and Korean Society of Neurogastroenterology and Motility served as the operating and development committees, respectively. The development of the guidelines began in June 2018, and a draft consensus based on the Delphi process was achieved in April 2019. The guidelines consist of 18 recommendations: 2 pertaining to the definition and epidemiology of achalasia, 6 pertaining to diagnoses, and 10 pertaining to treatments. The endoscopic treatment section is based on the latest evidence from meta-analyses. Clinicians (including gastroenterologists, upper gastrointestinal tract surgeons, general physicians, nurses, and other hospital workers) and patients could use these guidelines to make an informed decision on the management of achalasia.