Improving Drug Development for Rare Patients Post-COVID

Engaging the FDA from an early time point helped to paint a confident development roadmap as did the trailblazing work from an earlier program led by Dr. Timothy Yu at Boston Children's Hospital.2 Through this collaboration, a new way of advancing life-saving medicine is born-a furthering of the template first forged by Dr. Yu in an effort to define a path for families, academics and clinicians to treat even a single patient impacted by a genetic disease. Concepts from as the potential for 2D and 3D tissue modeling in lieu of an animal model to test efficacy to common delivery platforms in the case of AAV reducing the need for repetitive vector toxicology. A recent report by McKinsey cited that 45% of respondents (cell and gene therapy companies) expected delay's of 3-6 months on average for development programs.4 Diving into the details, delay's regarding site activation for clinical trials, patient recruitment for trials and follow up appointments of enrolled patients were top areas of delays with 55% of respondents citing these three areas as delayed. Lessons such as allowing virtual trials visits informed by diagnostic tests being done locally rather than having the patient go to a clinical trial site thereby limiting visits, trial burden and potential exposure (even in a post-COVID world).

American Christianity and the New Eugenics: Consumerism, Human Genetics, and the Challenge to Christian Personhood

Christian leaders and organizations sided overwhelmingly with politicians, scientists, social elites, and various progressive groups to champion the application of "scientific" methods designed to improve the nation's gene pool. Large numbers of Christians believed that genetic improvement of the human species was in keeping with God's command that humankind exercise dominion over creation.2 The unholy association of American Christianity with eugenics laboratories and associations was undermined by 1940 through rec-ognition of Nazi atrocities and realization of the extent to which eugenicists would go in attempts to accelerate and enhance what they saw as "natural" evolutionary processes. The generally favorable disposition of American Christians to the market's moral outcomes, even those that seem to test their reli-gious values, creates a climate in which churches increasingly will be challenged to protect the divine source of human dignity-what German theologian Helmut Thielicke called "alien dignity"-from functional and manipulable views of the person that arise alongside markets for genetic services.3 The entrepreneurial nature of the new "consumer" eugenics also highlights a divide that has formed between American churches and their memberships. Newborn screening and various forms of "reproductive genetics," oncology practices, treatments for auto-immune diseases, and even the response to the COVID-19 pandemic have been boons to this industry, not to mention growth in general interest among Americans eager to learn more about their genealogical and family histories.5 There is even a mail order industry for amateur geneticists who wish to experiment with gene editing in the privacy of their homes.6 It is consumer demand by individuals whose motivations range from the simple desire to experiment with cutting-edge technologies to those who envision possibilities for human "enhancement" to patients who face debil-itating genetic diseases, which fuels fear of a new eugenic age.

2022 Association of American Physicians Presidential Address Communicating as a physician-scientist

In a speech, 2022 Association of American Physicians Presidential Elizabeth McNally discusses the communication as a physician-scientist. Here, she shares that as a practicing physician, she finds mistrust is more commonplace than he has ever before experienced. She is especially concerned by physician-scientists who promote unsubstantiated ideas and claims and who intentionally fan the flames of suspicion and conspiracy. During this pandemic, certain physician-scientists vastly overstepped their knowledge and expertise, even promoting ideas that are not in the interest of human health. Some pushed false beliefs about "herd immunity" of populations who were "protected" and did not need vaccines. As a community of scientifically oriented practitioners, people hold a responsibility to counter these claims and to correct those who promote these falsehoods.

Low-intensity Aerobic Exercises during COVID-19 Pandemic in Children with Duchenne Muscular Dystrophy: A Home based Study

Duchenne muscular dystrophy (DMD) is a rare genetic disorder that affects about 0.8 million Indian children. The incidence rate of 1:3500 male births is the most common form of all muscular dystrophies. Covid-19 pandemic cause profound devastation to the lives of DMD children. The muscles are weaker in DMD, and the children are more prone to lung infections. Coronavirus (COVID-19) is a severe lung infection that disturbs the entire function of the World. DMD already has weakness in major muscles, including the respiratory. So, the study aims to identity the effect of low-intensity aerobic exercises in children with DMD. This is a home-based pilot study with 11 DMD children and wheelchair dependent since, for ten years, they have been on continuous rehabilitation and monitoring. When the pandemic was declared in India in March 2020, all children were given clear notes on the disease and its severity to the parents. Self-created quarantine exercise protocol, which includes Limb exercises, breathing exercises, trunk mobility exercises, and positioning, was taught along with a logbook given to all the children. Video calls, and WhatsApp videos, were used to monitor them regularly. The physiotherapist made a personal visit in June 2020 to review the exercises, and subsequently on Aug 20, Oct 20, Dec 20, Feb 21, and May 21. Observations are detailed here. The infection rate was 3 out of 9, and they got admitted to the hospital for other illnesses. All the children noted Flu infection but recovered within ten days without hospitalization. The parents monitored their SPo2 and temperature and updated them in the logbook. A lung function test was done using a handheld incentive spirometer during the personnel visit by the therapist and found satisfactory. The study concluded a significant improvement in the DMD children following low-intensity and quarantine exercises.

Forthcoming Articles

B Neurological and neurophysiological changes associated with SARS-CoV-2 infection: New observations, new mechanisms b Muhammed Ali Haidar, Hussam Jourdi, Zeinab Haj Hassan, OHanes Ashekyan, Manal Fardoun, Mark Wehbe, Ghassan Dbaibo, Hassan Zaraket, Ali Eid, & Firas Kobeissy B Circular RNAs in the brain: A possible role in memory? b Esmi Zajaczkowski & Timothy Bredy B Heart matters: Cardiac dysfunction and other autonomic changes in Parkinson's disease b Martin Trinidad Herrero, Valeria Gonçalves, Lorena Cuenca-Bermejo, Emiliano Fernandez-Villalba, Sebastian Martin-Balbuena, Maria da Silva Fernandes, & Carla Scorza B Complex inclusion bodies and defective proteome hubs in neurodegenerative disease: New clues, new challenges b Amit Mishra, Arun Upadhyay, Naveen Sundaria, Rohan Dhiman, Vijay Prajapati, & Amit Prasad B Brains that fire together wire together: Inter-brain plasticity underlies learning in social interactions b Simone Shamay-Tsoory B Animal and cellular models of Alzheimer's disease: Progress and future approaches b David Baglietto-Vargas, Laura Trujillo-Estrada, Elisabeth Sanchez-Mejias, Raquel Sanchez-Varo, Juan Antonio Garcia-Leon, Cristina Nuñez-Diaz, Jose Carlos Davilla, Javier Vitorica, Frank LaFerla, Ines Moreno-Gonzalez, & Antonia Gutierrez B Neuroscience - The new English major?. [Extracted from the article] Copyright of Neuroscientist is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Telegenetics and COVID 19: Through the Pandemic and Beyond

Introduction - The COVID 19 pandemic led to restrictions on the conventional ways of healthcare delivery. Telemedicine provided a viable solution that was in line with the social distancing policies imposed to minimize disease transmission. This demanded physicians adapt to new ways of healthcare delivery. We surveyed geneticists across the country to determine their experience and to ascertain if telegenetics will be a lasting change. Materials and Methods - A 23 item standardized survey was distributed to various US-based geneticists via email and other social media platforms focusing on their experience of providing care via telemedicine. Results - We received 69 responses from physicians across 26 states. Of these, 91% practiced in academia. 70% responded that pediatric genetics takes up more than 50% of their practice. 68% had over 50% of their practice switch to telemedicine. 77% felt they could provide adequate care via telemedicine and 94% of providers would like to continue telemedicine post-pandemic. Conclusion - The future of telemedicine looks promising as the majority of clinicians would like to routinely use telemedicine post-pandemic. Uniform guidelines for use of telemedicine in genetics may need to be proposed by professional societies and supported by federal laws.

The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA.

BACKGROUND: Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. METHODS: To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients' relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. RESULTS: In total 199 participants-144 children and 45 adults-with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. CONCLUSIONS: Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.

Forthcoming Articles

B Neurological and neurophysiological changes associated with SARS-CoV-2 infection: New observations, new mechanisms b Muhammed Ali Haidar, Hussam Jourdi, Zeinab Haj Hassan, OHanes Ashekyan, Manal Fardoun, Mark Wehbe, Ghassan Dbaibo, Hassan Zaraket, Ali Eid, & Firas Kobeissy B Circular RNAs in the brain: A possible role in memory?. [Extracted from the article] Copyright of Neuroscientist is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

The association between different predictive biomarkers and mortality of COVID-19

BackgroundImmunocompromised individuals are expected to be more prone to severe diseases and, subsequently, death. Genetic disorders and polymorphisms in genes involved in the immune system, such as human leukocyte antigen (HLA), inflammatory cytokines, and killer-cell immunoglobulin-like receptors, can be involved in the immune system's response to various pathogens. In the current survey, the data were received from the world health organization, collected around the world.ResultsSpearman's coefficient correlation test for evaluating the relationship between the Daily Death Rates (DDR) and immunological variables showed a statistically significant correlation between the DDR and all immunological variables except TNFa857T, TNFa863A IL2330G, and IL2166T (P < 0.001). Also, there was a statistically significant correlation between the DDR and some HLA markers.ConclusionThis meta-analysis study shows that predictive biomarkers and mortality of COVID-19 are associated with HLA markers. However, these results should be confirmed in a more structured agreement. It is worth noting that the design of new studies should consider potential diseases with poor prognoses because they are related to these immune genetic markers.

Characteristics of Creutzfeldt-Jakob disease cases reported by surveillance network in China, 2020

Objective: To investigate the incidence, epidemiology and clinical characteristics of Creutzfeldt-Jakob disease (CJD) in China in 2020.

Antioxidants to prevent respiratory decline in people with Duchenne muscular dystrophy and progressive respiratory decline

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterised by progressive muscle weakness beginning in early childhood. Respiratory failure and weak cough develop in all patients as a consequence of muscle weakness leading to a risk of atelectasis, pneumonia, or the need for ventilatory support. There is no curative treatment for DMD. Corticosteroids are the only pharmacological intervention proven to delay the onset and progression of muscle weakness and thus respiratory decline in DMD. Antioxidant treatment has been proposed to try to reduce muscle weakness in general, and respiratory decline in particular. Objectives: To assess the effects of antioxidant agents on preventing respiratory decline in people with Duchenne muscular dystrophy during the respiratory decline phase of the condition. Search methods: We searched CENTRAL, MEDLINE, Embase, and two trials registers to 23 March 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs that met our inclusion criteria. We included male patients with a diagnosis of DMD who had respiratory decline evidenced by a forced vital capacity (FVC%) less than 80% but greater than 30% of predicted values, receiving any antioxidant agent compared with other therapies for the management of DMD or placebo. Data collection and analysis: Two review authors screened studies for eligibility, assessed risk of bias of studies, and extracted data. We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. The primary outcomes were FVC and hospitalisation due to respiratory infections. Secondary outcomes were quality of life, adverse events, change in muscle function, forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF). Main results: We included one study with 66 participants who were not co-treated with corticosteroids, which was the only study to contribute data to our main analysis. We also included a study that enrolled 255 participants treated with corticosteroids, which was only available as a press release without numerical results. The studies were parallel-group RCTs that assessed the effect of idebenone on respiratory function compared to placebo. The trial that contributed numerical data included patients with a mean (standard deviation) age of 14.3 (2.7) years at the time of inclusion, with a documented diagnosis of DMD or severe dystrophinopathy with clinical features consistent with typical DMD. The overall risk of bias across most outcomes was similar and judged as 'low'. Idebenone may result in a slightly less of a decline in FVC from baseline to one year compared to placebo (mean difference (MD) 3.28%, 95% confidence interval (CI) -0.41 to 6.97;64 participants;low-certainty evidence), and probably has little or no effect on change in quality of life (MD -3.80, 95% CI -10.09 to 2.49;63 participants;moderate-certainty evidence) (Pediatric Quality of Life Inventory (PedsQL), range 0 to 100, 0 = worst, 100 = best quality of life). As a related but secondary outcome, idebenone may result in less of a decline from baseline in FEV1 (MD 8.28%, 95% CI 0.89 to 15.67;53 participants) and PEF (MD 6.27%, 95% CI 0.61 to 11.93;1 trial, 64 participants) compared to placebo. Idebenone was associated with fewer serious adverse events (RR 0.42, 95% CI 0.09 to 2.04;66 participants;low-certainty evidence) and little to no difference in non-serious adverse events (RR 1.00, 95% CI 0.88 to 1.13;66 participants;low-certainty evidence) compared to placebo. Idebenone may result in little to no difference in change in arm muscle function (MD -2.45 N, 95% CI -8.60 to 3.70 for elbow flexors and MD -1.06 N, 95% CI -6.77 to 4.65 for elbow extensors;both 52 participants) compared to placebo. We found no studies evaluating the outcome hospitalisation due to respiratory infection. The second trial, involving 255 participants

Mechanisms of Bone Marrow Failure and Leukemia Progression in Primary Human Fanconi Anemia Stem Cells in Novel FA PDX Model

The goal of this research proposal is to provide better treatments for Fanconi Anemia (FA), an inherited bone marrow failure disorder that affects approximately 1 in 100,000 children. The combination of hematopoietic stress and inherent genomic instability leads to cancer and accumulation of genetic defects is likely the cause of AML progression. We proposed to study primary human cell defective in the FA pathway to delineate pathways of leukemia progression and eventually prevent progression to bone marrow failure or progression to leukemia. Our two aims are to 1)identify molecular vulnerabilities and genetic changes promoting oncogenesis in FA deficient CD34+ cells in vitro and to 2) determine molecular changes at the root of disease progression in primary human FA bone marrow and test potential therapeutic approaches in vivo in MISTRG-kitMUT mice. To achieve this goal we have to i) obtain primary FA patient cells and ii) generate human FANC gene KO CD34+ cells. Note that the COVID pandemic has significantly impaired our progress since 3/15/2020. We have focused our efforts on generating FA defective cells via two mechanisms: a) shRNA mediated knockdown and b) via CRISPR/Cas9 mediated deletion. We have encountered 2 difficulties which we are still addressing: inefficiency of deleting FA genes and selection against deleted cells;silencing of rescue lentiviral vectors in primary hematopoietic cells. With COVID all work had to halt and mouse work was minimal we are expanding colonies and actively transplanting primary FA samples with goal to further optimize engineering of FA samples and transplantation in MISTRG mice.

New evidence of genetic factors related to severe infection of novel Coronavirus

Since the end of 2019, new coronavirus pneumonia caused by infection with a new type of coronavirus has become widespread in the world, posing a serious threat to life and health. However, after individuals are infected with SARS-CoV-2, significantly different outcomes occur, which can manifest as simple, mild, common, severe, and dangerous pneumonia. Previous research published in the New England Journal of Medicine suggested that severe infections in individuals may be related to genetic variation, but the genetic contribution and associated mechanisms of severe COVID-19 is still not well understood. Recently, JeanLaurent Casanova's team at Rockefeller University performed genomic testing on 1,193 patients with new coronary pneumonia and found that the critically ill patients carried rare harmful mutations. These mutations originate from 13 loci and related genes that are enriched in the TLR3/IRF7-dependent type I interferon pathway. Further studies of the function of all 118 non-synonymous mutations at these 13 loci revealed that cells harboring these mutations were more susceptible to SARS-CoV-2. This study suggests that TLR3/IRF7-dependent interferon immunity associated with dsRNA sensing may play an important role in the control of SARS-CoV-2, and that genetic defects in these genes are implicated in immunity may be responsible for the development of severe COVID-19 in some individuals.

SARS-CoV-2 pandemic in the Brazilian community of rare diseases: A patient reported survey.

The COVID-19 pandemic has led to a reorganization of health systems to prioritize the fight against the virus. The adoption of social distancing interfered with the flow of existing policies, and may thus negatively affect the most vulnerable groups, such as the rare disease community. Aimming at characterizing the perception of the impact of COVID-19 on the health care of the Brazilian rare disease community, an online questionnaire addressed to patients with rare diseases and their caregivers was disseminated in the Brazilian territory between June 1st to July 5th, 2020. The questions dealt with the sanitary measures adopted; access to medical services; and mental suffering during the pandemic. The survey was answered by 1,466 participants (<18 yo = 53.3%) representing 192 rare diseases. Regarding physical distancing, 1,372 (93.6%) participants did not leave their residence, or did so only when essential; 1,321 (90.1%) always wore masks when leaving home. 1,042 (71.1%) and 995 (67.9%) participants, respectively, referred medical genetics appointments and rehabilitation therapies were postponed/canceled. Telemedicine was experienced by 1,026 (70%), and 68.3% agreed this is a good strategy for health care. Patients with Inborn Errors of Metabolism (IEM, n = 624, 42.5%) appear to have more access to information and ability to overcome difficulties, and feel less threatened, lonely and depressed than the non-IEM group (p < .05). There was an increment of the rare disease patients' vulnerability in the pandemic scenario. The cooperation of patients/caregivers along with adaptation of the health system is crucial and may be so even post-pandemic.

Recommended measures for the efficient care of patients with genetic disorders during the COVID-19 pandemic in low and middle income countries.

The coronavirus disease 2019 (COVID-19) emerged in early 2020 and since, has brought about tremendous cost to economies and healthcare systems universally. Reports of pediatric patients with inherited conditions and COVID-19 infections are emerging. Specific risks for morbidity and mortality that this pandemic carries for different categories of genetic disorders are still mostly unknown. Thus, there are no specific recommendations for the diagnosis, management, and treatment of patients with genetic disorders during the COVID-19 or other pandemics. Emerging publications, from Upper-Middle Income countries (UMIC), discuss the recent experiences of genetic centers in the continuity of care for patients with genetic disorders in the context of this pandemic. Many measures to facilitate the plan to continuous genetic care in a well-developed health system, may not be applicable in Low and Middle Income countries (LMIC). With poorly structured health systems and with the lack of established genetic services, the COVID-19 pandemic will easily exacerbate the access to care for patients with genetic disease in these countries. This article focuses on the unique challenges of providing genetic healthcare services during emergency situations in LMIC countries and provides practical preparations for this and other pandemic situations.