Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Gene therapy is at the cusp of a revolution for treating a large spectrum of CNS disorders by providing a durable therapeutic protein via a single administration. Adeno-associated virus (AAV)-mediated gene transfer is of particular interest as a therapeutic tool because of its safety profile and efficiency in transducing a wide range of cell types. The purpose of this review is to describe the most notable advancements in preclinical and clinical research on AAV-based CNS gene therapy and to discuss prospects for future development based on a new generation of vectors and delivery.

BackgroundMobile health (mHealth) is a rapidly emerging field with the potential to assist older adults in the management of chronic pain (CP) through enhanced communication with providers, monitoring treatment-related side effects and pain levels, and increased access to pain care resources. Little is currently known, however, about older adults’ attitudes and perceptions of mHealth or perceived barriers and facilitators to using mHealth tools to improve pain management.MethodsWe conducted six focus groups comprised of 41 diverse older adults (≥60 years of age) with CP. Participants were recruited from one primary care practice and two multiservice senior community day-visit centers located in New York City that serve older adults in their surrounding neighborhoods. Focus group discussions were recorded and transcribed, and transcriptions were analyzed using direct content analysis to identify and quantify themes.ResultsFocus group discussions generated 38 individual themes pertaining to the use of mHealth to help manage pain and pain medications. Participants had low prior use of mHealth (5% of participants), but the vast majority (85%) were highly willing to try the devices. Participants reported that mHealth devices might help them reach their healthcare provider more expeditiously (27%), as well as help to monitor for falls and other adverse events in the home (15%). Barriers to device use included concerns about the cost (42%) and a lack of familiarity with the technology (32%). Facilitators to device use included training prior to device use (61%) and tailoring devices to the functional needs of older adults (34%).ConclusionsThis study suggests that older adults with CP are interested and willing to use mHealth to assist in the management of pain. Participants in our study reported important barriers that medical professionals, researchers, and mHealth developers should address to help facilitate the development and evaluation of age-appropriate, and function-appropriate, mHealth devices for older persons with CP.

Evidence-based interventions (EBIs) are an important tool for community health practitioners, but there is often a mismatch between the population in which the EBI was validated and the target population in which it will be used. Methods of planned adaptation identify differences in the new target population and attempt to make changes to the EBI that accommodate these differences without diluting the program’s effectiveness. This article outlines an innovative method for eliciting ideas for program modifications and deciding on program changes. The Method for Program Adaptation through Community Engagement (M-PACE) uses systematic and detailed feedback from program participants to guide adaptation. The authors describe procedures for obtaining high-quality participant feedback and adjudicating recommendations to decide on program changes. M-PACE was developed as part of the adaptation of an evidence-based, arthritis self-management program for older adults. The application and results of the M-PACE method are presented using this case as an example.

Introduction Sanfilippo syndrome (MPS III) is a rare, degenerative condition characterized by symptoms impacting cognitive ability, mobility, behavior, and quality of life. Currently there are no approved therapies for this severe life-limiting disease. Integrating patient and caregiver experience data into drug development and regulatory decision-making has become a priority of the Food and Drug Administration and rare disease patient communities. Methods This study assesses parents’ perceptions of their child’s Sanfilippo syndrome disease-related symptoms using a research approach that is consistent with the Center for Drug Evaluation and Research (CDER) guidance. This study was initiated by the Cure Sanfilippo Foundation, and all steps in the research process were informed by a multidisciplinary advisory committee, with an objective of informing biopharmaceutical companies and regulatory agencies. We explored caregiver burden, symptoms with greatest impact, and meaningful but unmet treatment needs. Data were collected from 25 parents through three focus groups and a questionnaire. Transcripts were coded and analyzed using inductive thematic analysis, and descriptive analysis of quantitative data was conducted. Results Participating parents’ children ranged in age from 4 to 36 years. Participants endorsed high caregiving burden across all stages of the disease. Analysis revealed multiple domains of unmet need that impact child and family quality of life, including cognitive-behavioral challenges in communication, relationships, behavior, anxiety, and child safety; and physical health symptoms including sleep, pain, and mobility. Participants reported placing high value on incremental benefits targeting those symptoms, and on a treatment that would slow or stop symptom progression. Conclusion Even modest treatment benefits for Sanfilippo syndrome were shown to be highly valued. Despite high caregiver burden, most parents expressed a willingness to “try anything,” including treatments with potentially high risk profiles, to maintain their child’s current state. Electronic supplementary material The online version of this article (10.1007/s40120-020-00226-z) contains supplementary material, which is available to authorized users.