CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy.

EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children's normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease.

A Dedicated Multidisciplinary Growth and Feeding Clinic for Infants with Cleft Lip and/or Palate Demonstrates Need for Intervention.

OBJECTIVE: A Growth and Feeding Clinic (GFC) focused on early intervention around feeding routines in patients with cleft lip and/or palate (CL/P) was implemented. DESIGN: This study assessed the effect of preoperative feeding interventions provided by the GFC. SETTING: Tertiary academic center. METHODS: This study evaluated patients with CL/P who were cared for by the GFC and a control group of patients with CL/P. Weight-for-age (WFA) Z-score of less than -2.00 was used as a cutoff to classify patients who were underweight during the preoperative period. MAIN OUTCOME MEASURE: The number of underweight patients who were able to reach normal weight by the time of their cleft lip repair was used as the primary outcome measure. RESULTS: Within both the GFC and control groups, 25% of patients with CL/P were underweight as determined by WFA Z-score. GFC patients who were underweight received more clinic visits (P < .001) and GFC interventions (P < .001) compared to GFC patients who were normal weight. At the time of cleft lip surgery, 64.1% of GFC underweight patients were normal weight compared to 31.8% of control group underweight patients (P = .0187). CONCLUSION: This study showed that multidisciplinary care provided by the GFC was able to target preoperative nutritional interventions to the highest-risk patients, resulting in double the percentage of patients who were of normal weight at the time of their cleft lip repair. These results provide objective proof supporting the assertion that multidisciplinary team care of the infant with cleft leads to measurable improvement in outcomes.

Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study).

BACKGROUND: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain. PATIENTS: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. RESULTS: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients. CONCLUSION: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations.