Challenges in Treating Genodermatoses: New Therapies at the Horizon

Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a “read through” strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus.

Infantile acne is a medical problem that calls for therapy

Background: Acne vulgaris of infants is a well-recognized medical and cosmetic problem as it may cause severe scarring of the face. Hence medical treatment is essentially needed. Objective: To record all patients with infantile acne vulgaris and to do full demographic and clinical evaluation. Patients and methods:This is case series clinical descriptive study with interventional therapeutic trial that included all patients with infantile acne vulgaris that were seen during the period from Jan 2021 – September 2021 years. All demographic and clinical features were recorded. The clinical scoring of acne severity was done as follow:mild when the rash was mainly comedones,moderate mainly papules and pustules and severe mainly nodules and scarring. Any triggering factors were recorded including hormonal changes. Therapy was started by giving topical 2% clindamycin twice a day and oral trimethoprim-sulfamethoxazole suspension one teaspoonful twice a day for 1-2 months. Results: This study included 28 patients with infantile acne, with 19(67.86%) males and 9(32.14%) females with male to female ratio;2.1. The age of patients ranged from 1-24 months, with a mean 14.6 ±6.1.The duration of rash was ranged from 4-8 weeks. The commonest sites affected were cheeks in 27(96.4%) cases, followed by forehead in 8 (28.6%), then chin in 6 (23.1%), and nose 6 (23.1%) of the cases. Scoring of severity of acne showed moderate in 13(46.4%), followed by mild in 9 (32.1%), and sever in 6 (21.4%). The response to treatment was complete clearance in 15(53.6%) and partial response in 13(46.4%) of the patients while no adverse effects were observed. Conclusions: Infantile acne is not uncommon disease among infants where medical therapy is essentially needed especially in severe cases as to prevent facial scarring. Early diagnosis and treatment with oral trimethoprim-sulfamethoxazole suspension and topical 2% clindamycin lotion is an effective mode of therapy.

Use of Aqueous Extract of Wrightia tinctoria Leaves and Coconut Oil in Camel Mange

The present study was carried out during August 2019 to March 2020 for the diagnosis and therapeutic management of mange in camel. A total of fourteen positive cases of mange infestation were selected for the therapeutic trial. The therapeutic trial was carried out with the use of two different treatment viz., aqueous extract of Wrightia tinctoria (20%) and coconut oil in mangy camels. The mite count was performed on weekly interval up to five weeks. The camels had more than twenty Sarcoptic mites on day 0 (pre-treatment). The mite count was gradually decreased on fifth week and the mite reduction was 96.50% and 96.77% in group A & B, respectively. The haematology shows the significantly (p<0.05) increase in Hb, TEC, PCV, Neutrophils and Monocytes whereas, significantly (p<0.05) decreased in TLC, and Lymphocyte. The serological and mineral estimation shows the significant (p<0.05) increase in values of total protein, ALT and Zinc; whereas creatinine, AST and copper were decreased significantly (p<0.05). After treatment of mange infected camels with two different treatments the values of all these hemato-biochemical and micromineral constituents returned nearer to normal values of camels. Thus, aqueous extract of Wrightia tinctoria (20%) and coconut oil gave positive effect on mange infested camels.

Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction—A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial

Background Chronic Lung Allograft Dysfunction (CLAD) is a major obstacle for long term survival after lung transplantation (LTx). Besides Bronchiolitis Obliterans Syndrome, two other phenotypes of CLAD, restrictive allograft syndrome (RAS) and mixed phenotype, have been described. Trials to test in these conditions are desperately needed and analyzing natural outcome to plan such trials is essential. Methods We performed a retrospective analysis of functional outcome in bilateral LTx recipients with RAS and mixed phenotype, transplanted between 2009 and 2018 in five large European centers with follow- up spirometry up to 12 months after diagnosis. Based on these data, sample size and power calculations for randomized therapeutic trial was estimated using two imputation methods for missing values. Results Seventy patients were included (39 RAS and 31 mixed phenotype), median 3.1 years after LTx when CLAD was diagnosed. Eight, 13 and 25 patients died within 6, 9 and 12 months after diagnosis and a two patients underwent re-transplantation within 12 months leading to a graft survival of 89, 79 and 61% six, nine and 12 months after diagnosis, respectively. Observed FEV1 decline was 451 ml at 6 months and stabilized at 9 and 12 months, while FVC showed continuous decline. Using two methods of imputation, a progressive further decline after 6 months for FEV1 was noted. Conclusion The poor outcome of these two specific CLAD phenotypes suggests the urgent need for future therapeutic randomized trials. The number of missing values in a potential trial seems to be high and most frequently attributed to death. Survival may be used as an endpoint in clinical trials in these distinct phenotypes and imputation techniques are relevant if graft function is used as a surrogate of disease progression in future trials.

Prescreening to Increase Therapeutic Oncology Trial Enrollment at the Largest Public Hospital in the United States

PURPOSE: The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS: The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS: Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non–English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION: Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.

Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

With the aim of designing a preclinical study evaluating an intracerebral cell-based therapy for stroke, an observational study was performed in the rat suture model of ischemic stroke. Objectives were threefold: (i) to characterize neurofunctional and imaging readouts in the first weeks following transient ischemic stroke, according to lesion subtype (hypothalamic, striatal, corticostriatal); (ii) to confirm that intracerebral administration does not negatively impact these readouts; and (iii) to calculate sample sizes for a future therapeutic trial using these readouts as endpoints. Our results suggested that the most relevant endpoints were side bias (staircase test) and axial diffusivity (AD) (diffusion tensor imaging). Hypothalamic-only lesions did not affect those parameters, which were close to normal. Side bias in striatal lesions reached near-normal levels within 2 weeks, while rats with corticostriatal lesions remained impaired until week 14. AD values were decreased at 4 days and increased at 5 weeks post-surgery, with a subtype gradient: hypothalamic < striatal < corticostriatal. Intracerebral administration did not impact these readouts. After sample size calculation (18-147 rats per group according to the endpoint considered), we conclude that a therapeutic trial based on both readouts would be feasible only in the framework of a multicenter trial.

Efficacy of Silymarin and SAM in the Management of Hepatic Disorders in Dogs

Background: Treatment of canine liver diseases is often supportive and enables combinations of drug therapy and dietary support. Many nutraceutical compounds that have anti-oxidant properties have been suggested as supplements in animals suffering with hepatic diseases especially silymarin and S-adenosyl methionine The current study was aimed to evaluate therapeutic efficacy of certain nutraceuticals in the management of hepatic disorders in dogs. Methods: Dogs presented to Veterinary Hospital, Bhoiguda, Hyderabad with the clinical signs suggestive of hepatobiliary disorders were selected. Detailed history of the affected dogs was collected. Later, these cases were subjected for detailed clinical examination. While, apparently healthy dogs presented for general health checkup and vaccination with no clinical condition in the age group of 2-5 years were selected randomly as healthy control group for this study. Result: The present investigation was under taken to study the therapeutic efficacy of certain nutraceuticals in the management of hepatic disorders in dogs. Based on history, clinical signs, haemato biochemistry and ultrasonography, 32 dogs were histologically confirmed as hepatic disorders which formed the largest group. These dogs were selected for therapeutic trial. Apart from the specific drugs, addition of nutraceuticals like Silymarin and S-adenosyl methionine therapy was effective in the treatment of hepatic disorders.

Zinc-responsive acral hyperkeratosis as a mimicker of cutaneous tuberculosis

Zinc-responsive acral hyperkeratosis is regarded as a novel entity masquerading numerous skin disorders, such as psoriasis, acral necrolytic erythema, and tuberculosis. Tuberculosis itself is a great imitator and so is its cutaneous form. Herein, we present the case of a female misdiagnosed as a case of tuberculosis verrucosa cutis due to clinical, biochemical, and histopathological features. The patient completed a full course of anti-tubercular therapy without an improvement and showed a dramatic response after a therapeutic trial of oral zinc. Thus, the patient was diagnosed as a case of zinc-responsive acral hyperkeratosis. In any form of acral hyperkeratotic lesions, zinc-responsive acral hyperkeratosis must be considered as a differential diagnosis.

Using Biomarkers to Predict Memantine Effects in Alzheimer’s Disease: A Proposal and Proof-Of-Concept Demonstration

Memantine’s benefits in Alzheimer’s disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual’s clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.