scholarly journals Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Maike F. Dohrn ◽  
Jessica Medina ◽  
Karmele R. Olaciregui Dague ◽  
Ernst Hund
Keyword(s):  
Muscular Atrophy ◽  
Systemic Disease ◽  
Treatment Options ◽  
Great Success ◽  
Transthyretin Amyloidosis ◽  
Open Questions ◽  
Liver Disease Progression ◽  
Allele Specific ◽  
The Central Nervous System ◽  
To Come

AbstractHereditary transthyretin (TTR) amyloidosis (ATTRv) is an autosomal dominant, systemic disease transmitted by amyloidogenic mutations in the TTR gene. To prevent the otherwise fatal disease course, TTR stabilizers and mRNA silencing antisense drugs are currently approved treatment options. With 90% of the amyloidogenic protein produced by the liver, disease progression including polyneuropathy and cardiomyopathy, the two most prominent manifestations, can successfully be halted by hepatic drug targeting or—formerly—liver transplantation. Certain TTR variants, however, favor disease manifestations in the central nervous system (CNS) or eyes, which is mostly associated with TTR production in the choroid plexus and retina. These compartments cannot be sufficiently reached by any of the approved medications. From liver-transplanted patients, we have learned that with longer lifespans, such CNS manifestations become more relevant over time, even if the underlying TTR mutation is not primarily associated with such. Are we therefore creating a new phenotype? Prolonging life will most likely lead to a shift in the phenotypic spectrum, enabling manifestations like blindness, dementia, and cerebral hemorrhage to come out of the disease background. To overcome the first therapeutic limitation, the blood–brain barrier, we might be able to learn from other antisense drugs currently being used in research or even being approved for primary neurodegenerative CNS diseases like spinal muscular atrophy or Alzheimer’s disease. But what effects will unselective CNS TTR knock-down have considering its role in neuroprotection? A potential approach to overcome this second limitiation might be allele-specific targeting, which is, however, still far from clinical trials. Ethical standpoints underline the need for seamless data collection to enable more evidence-based decisions and for thoughtful consenting in research and clinical practice. We conclude that the current advances in treating ATTRv amyloidosis have become a meaningful example for mechanism-based treatment. With its great success in improving patient life spans, we will still have to face new challenges including shifts in the phenotype spectrum and the ongoing need for improved treatment precision. Further investigation is needed to address these closed barriers and open questions.

scholarly journals Amyloidosis with Cardiac Involvement: Identification, Characterization, and Management

2021 ◽  
Author(s):  
Faizi Jamal ◽  
Michael Rosenzweig
Keyword(s):  
Cardiac Amyloidosis ◽  
Systemic Disease ◽  
Treatment Options ◽  
Diagnostic Algorithm ◽  
Transthyretin Amyloidosis ◽  
Cardiac Amyloid ◽  
Medical Interventions ◽  
Light Chain Disease ◽  
Organ Response ◽  
New Treatment

Abstract Purpose of Review Amyloidosis is a protein deposition disease whereby a variety of precursor proteins form insoluble fibrils that deposit in tissues, causing organ dysfunction and, many times, death. Accurate characterization of the disease based on the nature of the precursor protein, organ involvement, and extent of disease is paramount to guide management. Cardiac amyloidosis is critical to understand because of its impact on prognosis and new treatment options available. Recent Findings New imaging methods have proven to be considerably valuable in the identification of cardiac amyloid infiltration. For treating clinicians, a diagnostic algorithm for patients with suspected amyloidosis with or without cardiomyopathy is shown to help classify disease and to direct appropriate genetic testing and management. For patients with light chain disease, recently introduced treatments adopted from multiple myeloma therapies have significantly extended progression-free and overall survival as well as organ response. In addition, new medical interventions are now available for those with transthyretin amyloidosis. Summary Although cardiac amyloidosis contributes significantly to the morbidity and mortality associated with systemic disease, new tools are available to assist with diagnosis, prognosis, and management.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

2021 ◽  
Vol 22 (14) ◽  
pp. 7536
Author(s):  
Inez Wens ◽  
Ibo Janssens ◽  
Judith Derdelinckx ◽  
Megha Meena ◽  
Barbara Willekens ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Tailored Treatment ◽  
Key Issues ◽  
The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

scholarly journals Expert Opinion on the Management of Non-Alcoholic Fatty Liver Disease (NAFLD) in the Middle East with a Focus on the Use of Silymarin

2021 ◽  
Vol 12 (2) ◽  
pp. 155-165
Author(s):  
Ahmed Hashem ◽  
Yogesh Shastri ◽  
Malfi Al Otaibi ◽  
Elwin Buchel ◽  
Hussam Saleh ◽  
...  
Keyword(s):  
Liver Disease ◽  
Middle East ◽  
Fatty Liver Disease ◽  
Expert Panel ◽  
Treatment Options ◽  
Current Treatment ◽  
Alcoholic Fatty Liver ◽  
Liver Disease Progression ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty disease (NAFLD) is amongst the leading causes of chronic liver disease worldwide. The prevalence of NAFLD in the Middle East is 32%, similar to that observed worldwide. The clinicians in this region face several challenges in diagnosing and treating patients with NAFLD. Additionally, there are no national or regional guidelines to address the concerns faced with current treatment options. Silymarin, derived from milk thistle, provides a rational and clinically proven approach to hepatoprotection. This article focuses on addressing regional diagnostic challenges and provides clear guidance and potential solutions for the use of Silymarin in the treatment of NAFLD in the Middle East. Both clinical and preclinical studies have highlighted the efficiency of Silymarin in managing NAFLD by reducing liver disease progression and improving patient symptoms and quality of life, alongside being safe and well tolerated. An expert panel of professionals from the Middle East convened to establish a set of regional-specific diagnostics. A consensus was established to aid general physicians to address the diagnostic challenges in the region. In conclusion, Silymarin can be considered beneficial in treating NAFLD and should be initiated as early as possible and continued as long as necessary.

scholarly journals Massachusetts’ Findings from Statewide Newborn Screening for Spinal Muscular Atrophy

2021 ◽  
Vol 7 (2) ◽  
pp. 26
Author(s):  
Jaime E. Hale ◽  
Basil T. Darras ◽  
Kathryn J. Swoboda ◽  
Elicia Estrella ◽  
Jin Yun Helen Chen ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Newborn Screening ◽  
New England ◽  
Screening Program ◽  
Muscular Atrophy ◽  
Treatment Options ◽  
Newborn Screening Program ◽  
Treatment Protocols ◽  
Screening Algorithm ◽  
New Treatment

Massachusetts began newborn screening (NBS) for Spinal Muscular Atrophy (SMA) following the availability of new treatment options. The New England Newborn Screening Program developed, validated, and implemented a screening algorithm for the detection of SMA-affected infants who show absent SMN1 Exon 7 by Real-Time™ quantitative PCR (qPCR). We screened 179,467 neonates and identified 9 SMA-affected infants, all of whom were referred to a specialist by day of life 6 (average and median 4 days of life). Another ten SMN1 hybrids were observed but never referred. The nine referred infants who were confirmed to have SMA were entered into treatment protocols. Early data show that some SMA-affected children have remained asymptomatic and are meeting developmental milestones and some have mild to moderate delays. The Massachusetts experience demonstrates that SMA NBS is feasible, can be implemented on a population basis, and helps engage infants for early treatment to maximize benefit.

scholarly journals Cardiac Amyloidosis Therapy: A Systematic Review

2021 ◽  
Vol 11 (1) ◽  
pp. 10-17
Author(s):  
Franco Iodice ◽  
Marco Di Mauro ◽  
Marco Giuseppe Migliaccio ◽  
Angela Iannuzzi ◽  
Roberta Pacileo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systematic Review ◽  
Cardiac Amyloidosis ◽  
Restrictive Cardiomyopathy ◽  
Novel Therapies ◽  
Preserved Ejection Fraction ◽  
Cardiac Damage ◽  
Transthyretin Amyloidosis ◽  
To Come ◽  
Almost All

Heart involvement in Cardiac Amyloidosis (CA) results in a worsening of the prognosis in almost all patients with both light-chain (AL) and transthyretin amyloidosis (ATTR). The mainstream CA is a restrictive cardiomyopathy with hypertrophic phenotype at cardiac imaging that clinically leads to heart failure with preserved ejection fraction (HFpEF). An early diagnosis is essential to reduce cardiac damage and to improve the prognosis. Many therapies are available, but most of them have late benefits to cardiac function; for this reason, novel therapies are going to come soon.

scholarly journals In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine

2021 ◽  
Author(s):  
Antonio Munafò ◽  
Stefano Frara ◽  
Norberto Perico ◽  
Rosaria Di Mauro ◽  
Monica Cortinovis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Options ◽  
Public Health Problem ◽  
Cardiovascular Death ◽  
Regulation Of Transcription ◽  
Major Public Health Problem ◽  
Obese Patients ◽  
Ephedra Sinica ◽  
The Central Nervous System ◽  
Treatment Of Obesity

AbstractObesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with β3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.

scholarly journals Global Spread of Mutant PfCRT and Its Pleiotropic Impact on Plasmodium falciparum Multidrug Resistance and Fitness

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Satish K. Dhingra ◽  
Stanislaw J. Gabryszewski ◽  
Jennifer L. Small-Saunders ◽  
Tomas Yeo ◽  
Philipp P. Henrich ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Treatment Options ◽  
Specific Treatment ◽  
Whole Genome Sequence ◽  
Content Type ◽  
Allelic Distribution ◽  
Population Structures ◽  
Allele Specific ◽  
Specific Parasite

Our study defines the allelic distribution of pfcrt, an important mediator of multidrug resistance in Plasmodium falciparum, in Africa and Asia. We leveraged whole-genome sequence analysis and gene editing to demonstrate how current drug combinations can select different allelic variants of this gene and shape region-specific parasite population structures. We document the ability of PfCRT mutations to modulate parasite susceptibility to current antimalarials in dissimilar, pfcrt allele-specific ways. This study underscores the importance of actively monitoring pfcrt genotypes to identify emerging patterns of multidrug resistance and help guide region-specific treatment options.

scholarly journals Epidermal Growth Factor rs4444903 A>G Gene Polymorphism Association with Chronic Hepatitis B Liver Disease Progression among Egyptian Children: A Multicenter Study

2021 ◽  
Vol 11 (1) ◽  
pp. 63-68
Author(s):  
Amal A. Mohamed ◽  
Gehan L.A. Hakeem ◽  
Gihan M. Babrs ◽  
Laila E. Abolfotoh ◽  
Nageh M. Shehata ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Genotypic Frequency ◽  
Liver Disease Progression ◽  
Egyptian Children ◽  
Chronic Hepatitis B Virus ◽  
Genes Encoding ◽  
Allele Specific ◽  
Specific Amplification

Background: Polymorphisms of genes encoding the pro-inflammatory and anti-inflammatory cytokines can affect the clinical presentation of the infection. We aimed to assess the role of EGF gene single-nucleotide polymorphism in the outcome of chronic hepatitis B virus (HBV) infection in children. Methods: One hundred HBV-infected children and 75 healthy matched controls were enrolled in this prospective study. Patients included 18 chronic inactive and 82 chronic active carriers. EGF rs4444903 A>G genotypes were determined using allele-specific amplification. Results: Significant differences regarding EGF genotypic frequency (p=0.001) in patients compared to controls (p=0.001). Eighteen percent were inactive, and 82% were active carriers. AA, AG and GG genotypic frequency were 66.7%, 33.3%, 0% and were 3.7%, 37.8% and 58.5% in the inactive and active carriers, respectively, with significant differences regarding AA, AG, GG genotypic frequency (p=0.001 for all). EGF AA, AG, GG genotypes frequency were 1.9%, 33.3%, and 64.8%, respectively, with significant differences between cirrhotic and non-cirrhotic patients regarding AA, AG, GG genotypic frequency (p=0.001 for all). Conclusion: Increased G allele frequency in EGF rs4444903 A > G polymorphism in HBV- Egyptian children is associated with worse outcomes.

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