Dr Hana Hassanin

Aims KCL‐286 is an orally available agonist that activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population. Methods The design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. Results At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. Conclusion KCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI.

Background Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p

Background A preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV. Methods This first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18–45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4 × 1012 vector genomes; group B, 4 × 1013 vector genomes; group C, 8 × 1013 vector genomes; and group D, 1·2 × 1014 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov, number NCT01937455. Findings Between Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected. Interpretation Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies.

Research ethics committees exist internationally to review research proposals to protect the rights and safety of human participants and researchers involved in research. These committees recruit a panel of expert and lay members, mostly on an unpaid voluntary basis, with relevant scientific experience to appraise these studies. Contemporary data in the UK show that women and people over 55 years old are overrepresented in these committee panels in the Health Research Authority, suggesting that there are potential barriers to inclusivity and participation. A variety of global approaches to tackle these barriers include targeting specific populations, such as faith or community leaders, or implementing quotas have been adopted. Further research is needed to understand likely barriers preventing participation in research ethics committees in the UK and how they may be overcome.

This chapter sheds light on the milestones and history of mRNA vaccine development. The challenges encountered with an mRNA-based vaccine, and how MERS (Middle East Respiratory Syndrome) and SARS (Severe Acute Respiratory Syndrome) impacted the success of finding quick and effective vaccines, are described. I show how an already existing platform was modified to target the new coronavirus pathogen, and what factors played a crucial role in public acceptance or refusal of the RNA-based vaccines.

Introduction Longitudinal monitoring of vital signs provides a method for identifying changes to general health in an individual and particularly so in older adults. The nocturnal sleep period provides a convenient opportunity to assess vital signs. Contactless technologies that can be embedded into the bedroom environment are unintrusive and burdenless and have the potential to enable seamless monitoring of vital signs. To realise this potential, these technologies need to be evaluated against gold standard measures and in relevant populations. Methods We evaluated the accuracy of heart rate and breathing rate measurements of three contactless technologies (two under-mattress trackers: Withings sleep analyser (WSA) and Emfit QS (Emfit) and a bedside radar: Somnofy) in a sleep laboratory environment and assessed their potential to capture vital signs (heart rate and breathing rate) in a real-world setting. Data were collected in 35 community dwelling older adults aged between 65 and 83 years (mean ± SD: 70.8 ± 4.9; 21 men) during a one-night clinical polysomnography (PSG) in a sleep laboratory, preceded by 7 to 14 days of data collection at-home. Several of the participants had health conditions including type-2 diabetes, hypertension, obesity, and arthritis and ≈49% (n = 17) had moderate to severe sleep apnea while ≈29% (n = 10) had periodic leg movement disorder. The under-mattress trackers provided estimates of both heart rate and breathing rate while the bedside radar provided only breathing rate. The accuracy of the heart rate and breathing rate estimated by the devices was compared to PSG electrocardiogram (ECG) derived heart rate (beats per minute, bpm) and respiratory inductance plethysmography thorax (RIP thorax) derived breathing rate (cycles per minute, cpm). We also evaluated breathing disturbance indices of snoring and the apnea-hypopnea index (AHI) available from the WSA. Results All three contactless technologies provided acceptable accuracy in estimating heart rate [mean absolute error (MAE) < 2.2 bpm and mean absolute percentage error (MAPE) < 5%] and breathing rate (MAE ≤ 1.6 cpm and MAPE < 12%) at 1 minute resolution. All three contactless technologies were able to capture changes in heart rate and breathing rate across the sleep period. The WSA snoring and breathing disturbance estimates were also accurate compared to PSG estimates (R-squared: WSA Snore: 0.76, p < 0.001; WSA AHI: 0.59, p < 0.001). Conclusion Contactless technologies offer an unintrusive alternative to conventional wearable technologies for reliable monitoring of heart rate, breathing rate, and sleep apnea in community dwelling older adults at scale. They enable assessment of night-to-night variation in these vital signs, which may allow the identification of acute changes in health, and longitudinal monitoring which may provide insight into health trajectories.

Study Objective: To compare the 24-hour sleep assessment capabilities of two contactless sleep technologies (CSTs) to actigraphy in community-dwelling older adults. Methods: We collected 7 to 14 days of data at home from 35 older adults (age: 65-83), some with medical conditions, using Withings Sleep Analyser (WSA, n=29), Emfit-QS (Emfit, n=17), a standard actigraphy device (Actiwatch Spectrum [AWS, n=34]) and a sleep diary. We compared nocturnal and daytime sleep measures estimated by the CSTs and actigraphy without sleep diary information (AWS-A) against sleep diary assisted actigraphy (AWS|SD). Results: Compared to sleep diary, both CSTs accurately determined the timing of nocturnal sleep (ICC: going to bed, getting out of bed, time in bed > 0.75) whereas the accuracy of AWSA was much lower. Compared to AWS|SD, the CSTs overestimated nocturnal total sleep time (WSA: +92.71±81.16 min; Emfit: +101.47±75.95 min) as did AWS-A (+46.95±67.26 min). The CSTs overestimated sleep efficiency (WSA: +9.19±14.26 %; Emfit: +9.41±11.05 %) whereas AWS-A estimate (-2.38±10.06 %) was accurate. About 65% (n=23) of participants reported daytime naps either in-bed or elsewhere. About 90% in-bed nap periods were accurately determined by WSA while Emfit was less accurate. All three devices estimated 24-h sleep duration with an error of ≈10% compared to the sleep diary. Conclusions: CSTs accurately capture the timing of in-bed nocturnal sleep periods without the need for sleep diary information. However, improvements are needed in assessing parameters such as total sleep time, sleep efficiency and naps before these CSTs can be fully utilized in field settings. Statement of Significance: Contactless sleep technologies that do not pose a burden on participants are promising tools for longitudinal monitoring of sleep in the community. In a comparison with sleep diary assisted actigraphy, we show that two under-mattress devices used without sleep diary information, provide accurate information on nocturnal sleep timing and 24-hr bed presence. The study population comprised community-dwelling older adults, several of whom had medical conditions such as sleep apnea, arthritis, and type-2 diabetes, which adds to the relevance of these data. With further improvements in their performance, these unobtrusive sleep technologies have significant potential for at scale and longitudinal monitoring of 24-h sleep-wake patterns in older adults without the burden of completing sleep diaries.

Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18–75. A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 μg then 10 μg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). 216 healthy individuals (median age 51 years) received 1.0 μg followed by 10.0 μg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18–75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 μg dose with a ≥0.5log10 increase in 71% (22/31). Encapsulated saRNA was well tolerated and immunogenic in adults aged 18–75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 μg followed by 10.0 μg. Boosting of S IgG antibodies was observed with a single 1.0 μg injection in those with pre-existing immune responses. Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth.

Background: Contactless sleep technologies (CSTs) hold promise for longitudinal, unobtrusive sleep monitoring in health and disease at scale, particularly in older people where the increased incidence of sleep abnormalities with aging is considered a risk factor for several neurodegenerative disorders. However, few CST have been evaluated in older people. Objective: To evaluate the performance of three contactless sleep technologies (a bedside radar [Somnofy] and two under-mattress devices [Withings Sleep Analyser and Emfit-QS]) compared to polysomnography (PSG) and actigraphy [Actiwatch Spectrum] recorded during a first night in a sleep laboratory, 10-hour time in bed protocol, which induced mild sleep disturbance. Methods: Thirty-five older men and women (70.8±4.9 years; 14 women) several of whom had comorbidities and/or sleep apnoea, participated in the study. Devices were evaluated by estimating a range of performance metrics for classification of sleep vs wake, and NREM and REM sleep stages (sleep summary and epoch by epoch concordance) and comparing to PSG metrics. Results: All three CSTs overestimated total sleep time (bias [mean]: > 90 min) and sleep efficiency (bias: > 13 %) with an associated underestimation of wake after sleep onset (bias: > 50 min). Sleep onset latency was accurately detected by the bedside radar (bias: 16 mins). CSTs did not perform as well as actigraphy in estimating the all-night sleep summary measures. The bedside radar performed better in discriminating sleep vs wake (MCC [mean and 95% CI]: 0.63 [0.57 0.69]) than the under-mattress devices (MCC: =0.41 [0.36 0.46]; Emfit-QS =0.35 [0.26 0.43]). Accuracy of identifying REM and Light sleep was poor across all CSTs while deep sleep was predicted with moderate accuracy (MCC: >0.45) by both Somnofy and Withings Sleep Analyser. The deep sleep duration estimates of Somnofy was found to be significantly correlated (r2=0.6, p

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

Circadian rhythms, metabolism, and nutrition are closely linked.1 Timing of a 3-meal daily feeding pattern synchronises some human circadian rhythms.2 Despite animal data showing anticipation of food availability, linked to a Food Entrainable Oscillator3, it is unknown whether human physiology predicts mealtimes and restricted food availability. In a controlled laboratory protocol, we tested the hypothesis that the human circadian system anticipates large meals. Twenty-four male participants undertook an 8-day laboratory study, with strict sleep-wake schedules, light-dark schedules, and food intake. For six days, participants consumed either hourly small meals throughout the waking period, or two large daily meals (7.5 and 14.5-h after wake-up). All participants then undertook a 37-hour constant routine. Interstitial glucose was measured every 15 minutes throughout the protocol. Hunger was assessed hourly during waking periods. Saliva melatonin was measured in the constant routine. During the 6-day feeding pattern, both groups exhibited increasing glucose concentration early each morning. In the small meal group, glucose concentrations continued to increase across the day. However, in the large meal group, glucose concentrations decreased from 2-h after waking until the first meal. Average 24-h glucose concentration did not differ between groups. In the constant routine, there was no difference in melatonin onset between groups, but antiphasic glucose rhythms were observed, with low glucose at the time of previous meals in the large meal group. Moreover, in the large meal group, constant routine hunger scores increased before the predicted meal times. These data support the existence of human food anticipation.