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New opportunities have arisen for development of therapies for rare diseases with the increased focus and progress in the field. However, standardised framework integrating individual initiatives has not been formed. We present lessons learned and best practice from a collaborative success case in developing a treatment for a rare genetic disease. Our unique consortium model incorporated several of the identified developments under one project, DevelopAKUre, truly bringing together academia, industry and patient organisations in clinical drug development. We found that the equal partnership between all parties in our consortium was a key success factor creating a momentum based on a strong organisational culture where all partners had high engagement and taking ownership of the entire programme. With an agreed mutual objective, this provided synergies through connecting the strengths of the individual parties. Another key success factor was the central role of the patient organisation within the management team, and their unique study participants’ advocacy role securing the understanding and meeting the needs of the clinical study participants in real-time. This resulted in an accelerated enrolment into the clinical studies with a high retention rate allowing for delivery of the programme with significantly improved timelines. Our project was partly funded through an external EU research grant, enabling our model with equal partnership. Further attention within the community should be given to establishing a functional framework where sustainable funding and risk sharing between private and public organisations allow for our model to be replicated.

In the original publication [...]

Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype–phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients.

Background In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply \"cross-talks\" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells. Methods mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB]) were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63) showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP), procollagen type 1 amino-terminal propeptides (P1NP), and osteocalcin production. Results The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor) expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and obestatin. ALP showed higher levels in Saos-2 after GIP, GHR and OB and in TE-85 after GHR. P1NP showed higher levels after GIP and OB in Saos-2. Decreased levels of P1NP were observed in TE-85 and MG-63 after GLP-1, GLP-2 and OB. MG-63 showed opposite responses in osteocalcin levels after GLP-2. Conclusions These results suggest that osteoblast activity modulation varies according to different development stage under different nutrition related-peptides.

Little is documented on whether nitisinone‐induced hypertyrosinaemia alters cognitive functioning or leads to worsening depression in alkaptonuria (AKU). Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) and Beck Depression Inventory‐II (BDI‐II) assessments were performed before and annually following treatment with nitisinone 2 mg daily to assess the impact on cognitive functioning and severity of depression. Serum tyrosine concentrations were also measured annually. WAIS‐IV: 63 patients (27 females/36 males: mean age[years] [±standard deviation, range] 55.7[13.7, 26–79]; 60.3[9.6, 19–75]) were included at baseline for assessment of: verbal comprehension (VC), perceptual reasoning (PR), working memory (WM), and processing speed (PS) using separate indices. Over the 6‐year period studied 43, 39, 36, 29, 26 and 15 patients had annual assessments. Using a longitudinal model (age and sex adjusted) no significant differences were observed in any of the indices over this period, apart from VC which showed a significant increase after adjustment for sex (p < 0.05). BDI‐II: 74 patients (32 females/42 males: mean age[years] [±standard deviation, range] 56.1[13.2, 26–79]; 42 males, 51.5[16.3, 19–70]) were included at baseline. Over the 7‐year period studied 48, 47, 38, 34, 32, 24 and 12 patients had annual assessments. No significant differences in BDI‐II scores were observed when compared to baseline. Hypertyrosinaemia was observed in all patients following treatment with nitisinone (p < 0.001, at all annual visits). Serum tyrosine was not correlated with WAIS‐IV sub‐test indices or BDI‐II scores pre‐ or post‐nitisinone therapy. These findings suggest that treatment with nitisinone does not affect cognitive functioning and or lead to increased severity of depression.

Background Accurately recognizing that a person may be dying is central to improving their experience of care at the end-of-life. However, predicting dying is frequently inaccurate and often occurs only hours or a few days before death. Methods We performed urinary metabolomics analysis on patients with lung cancer to create a metabolite model to predict dying over the last 30 days of life. Results Here we show a model, using only 7 metabolites, has excellent accuracy in the Training cohort n  = 112 (AUC = 0·85, 0·85, 0·88 and 0·86 on days 5, 10, 20 and 30) and Validation cohort n  = 49 (AUC = 0·86, 0·83, 0·90, 0·86 on days 5, 10, 20 and 30). These results are more accurate than existing validated prognostic tools, and uniquely give accurate predictions over a range of time points in the last 30 days of life. Additionally, we present changes in 125 metabolites during the final four weeks of life, with the majority exhibiting statistically significant changes within the last week before death. Conclusions These metabolites identified offer insights into previously undocumented pathways involved in or affected by the dying process. They not only imply cancer’s influence on the body but also illustrate the dying process. Given the similar dying trajectory observed in individuals with cancer, our findings likely apply to other cancer types. Prognostic tests, based on the metabolites we identified, could aid clinicians in the early recognition of people who may be dying and thereby influence clinical practice and improve the care of dying patients. Coyle et al. utilize urinary metabolomics analysis to predict dying over the last 30 days of life in patients with lung cancer and provide insights into the dying process. The metabolite model provides prognostic information at the end of life allowing for the early recognition of people who may be dying and improve the care of these patients. Plain Language Summary Recognizing when someone is nearing the end of life is important for providing better care, but it is often hard to predict accurately. In our study, we analyzed urine samples from lung cancer patients to develop a method that can predict when a person is in their last 30 days of life. We identified 7 key chemicals in the urine that helped us predict death with high accuracy. This method worked better than current tools and provided reliable predictions throughout the last month of life. We also found changes in many other chemicals in the final weeks. These findings could help doctors identify when a patient is dying earlier, leading to better care at the end of life.

Dear editor, On April 1st 2012, NHS England Highly Specialised Services (HSS) commissioned the National Alkaptonuria Service for adults in the Department of Clinical Biochemistry & Metabolic Medicine at the Royal Liverpool University Hospital. 1 The service is called the Robert Gregory National Alkaptonuria Centre (NAC) in memory of the alkaptonuria (AKU) patient who founded the Alkaptonuria Society (AKUS) in 2003.The AKUS is embedded in the NAC and crucial to its functioning and success, ensuring patients are at the centre of the service. The NAC has generated new knowledge about AKU and its management (Table S1); with a few examples being prevalent cataract before and after nitisinone, nitisinone-associated vitiligo, characterising spine and joint disease and demonstrating lack of cognitive impairment during nitisinone therapy of adults with AKU. 8–11 The NAC permitted research collaboration between the NAC and the University of Liverpool, allowing cutting edge research into AKU to be pioneered and carried out with examples including development of conditional mouse models of AKU including liver and kidney knockouts in which new therapies are tested such as tyrosine-reducing therapies, as well as enzyme replacement therapies involving gene and mRNA administration. 12 A new mechanism of joint damage in AKU was developed and found to apply in osteoarthritis. 13 Unachieved goals and further challenges: [...]we have developed an assay system using the MitraTM sampling device, which offers a more user-friendly and robust alternative. 14 Preliminary feedback from patients has been positive and we are in the process of integrating this into the patient pathway.

Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.

Homogentisic acid (HGA) lowering, disease modifying off‐label nitisinone therapy has been used in the United Kingdom National Alkaptonuria Centre (NAC) since 2012. This study evaluated the serendipitous observation of cataract in a large cohort of patients with the very rare disease alkaptonuria (AKU), over a 5‐year period. Patients with AKU who attended the NAC since 2012. Standard physical examination and ocular assessment, including photographs of the crystalline lens were taken before commencement of nitisinone 2 mg daily and annually over 5 years. Photographs were randomised and graded by two independent observers using the WHO cataract classification. AKU patients who did not receive nitisinone were included as a control group. HGA was measured on acidified 24 h urine (u‐HGA24) and HGA and tyrosine in fasting acidified serum samples (sHGA, sTYR) at each visit. Patients without suitable lens images were excluded. Cataract (mean grade 1) was noted at baseline in 47 out of 62 (76%) with a mean (SD) age of 44 (14) years. In nitisinone‐treated patients, there were significant increases in the mean grade of nuclear (0.18, p < 0.01) and cortical (0.38, p < 0.01) lens opacities over the mean duration of 4.93 years of the study. Worsening of the nuclear cataract and cortical lens opacities by at least 1 grade was noted in 14 out of 46 (30%) and 11 out of 46 (24%) patients, respectively. There is an increased prevalence and progression of cataract in AKU and a possible association of nitisinone with cataract progression.

Background Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared. Patients and methods Sixty‐nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24‐h urine homogentisic acid (uHGA24), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc. Results The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x‐axis was −132, −411, −295, and − 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p < 0.001) and the SONIA 2 (p < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively. Discussion The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively. Conclusion Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low‐protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone. Highlights Nitisinone 10 mg apparently slows alkaptonuria disease progression more than 2 mg in adults. Corneal keratopathy during nitisinone therapy was more common in men. Serum nitisinone concentrations increased significantly over time. Nitisinone may inhibit cytochrome P450 self catabolism.