A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models.

A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and deficiency of DNASE1L3, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association can be found in an ultrarare population of pediatric patients with DNASE1L3 deficiency who develop SLE, adult patients with loss-of-function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies against DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1-/-Dnase1L3-/- double-knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degraded genomic and mitochondrial cell-free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.

Resiliency outcomes after participation in an asynchronous web-based platform for adults with neurofibromatosis: The NF-Web study.

The purpose of this study was to analyze secondary resiliency and user experience outcomes from a novel, 8-week website-based mind-body intervention (NF-Web) for adults (18+) with neurofibromatosis (NF1, NF2, and schwannomatosis), a genetic, neurocutaneous disorder characterized by nerve sheath tumors of the central and peripheral nervous system. The study design was a secondary data analysis of a single-arm, early feasibility pilot study (September 2020-May 2021) for adults with NF (N = 28). Across participants, the mean age was 46 (SD = 13.67) and included 22 females and 6 males. Participants completed baseline and posttest assessments (t-tests), as well as exit interviews (exploratory rapid data analysis). Results demonstrated that participation was associated with pre-to-post improvements in gratitude, coping, and mindfulness (p < .05). Exit interviews indicated participant enjoyment and that many would recommend NF-Web to a friend. Participants found the website easy to navigate and enjoyed NF-Web's video format. Many found transcripts useful if they had hearing differences or if English was their second language. NF-Web demonstrated initial signals of improvement in resiliency outcomes and positive user experience. Future pilot RCTs will explore these changes by NF type.

"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.

Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.