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CNS Drugs Sep 2023The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic... (Review)
Review
The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABA receptors and includes Staccato alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABA receptor α and β subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.
Topics: Infant, Newborn; Humans; Epilepsy; gamma-Aminobutyric Acid; Epilepsies, Myoclonic; Epilepsies, Partial; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic
PubMed: 37603261
DOI: 10.1007/s40263-023-01025-4 -
Science Translational Medicine Jun 2023Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ()-mutant high-grade serous ovarian carcinoma (HGSC). However,...
Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ()-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase () and cyclin E1 () overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. reversion mutation in previously PARPi-treated -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with -mutant HGSC.
Topics: Animals; Female; Humans; Mice; Antineoplastic Agents; Biomarkers; BRCA1 Protein; Breast Neoplasms; Drug Resistance, Neoplasm; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 37343085
DOI: 10.1126/scitranslmed.add7872 -
JMIR Dermatology Oct 2023Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a... (Review)
Review
BACKGROUND
Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a red skin rash occurring on sun-exposed areas of the body, and an increased risk of cancer. CTE is one of many genodermatoses and photodermatoses associated with defects in DNA repair. CTE is caused by a mutation occurring in the BLM gene, which causes abnormal breaks in chromosomes.
OBJECTIVE
We aimed to analyze the existing literature on CTE to provide additional insight into its heredity, the spectrum of clinical presentations, and the management of this disorder. In addition, the gaps in current research and the use of artificial intelligence to streamline clinical diagnosis and the management of CTE are outlined.
METHODS
A literature search was conducted on PubMed, DOAJ, and Scopus using search terms such as "congenital telangiectatic erythema," "bloom syndrome," and "bloom-torre-machacek." Due to limited current literature, studies published from January 2000 to January 2023 were considered for this review. A total of 49 sources from the literature were analyzed.
RESULTS
Through this scoping review, the researchers were able to identify several publications focusing on Bloom syndrome. Some common subject areas included the heredity of CTE, clinical presentations of CTE, and management of CTE. In addition, the literature on rare diseases shows the potential advancements in understanding and treatment with artificial intelligence. Future studies should address the causes of heterogeneity in presentation and examine potential therapeutic candidates for CTE and similarly presenting syndromes.
CONCLUSIONS
This review illuminated current advances in potential molecular targets or causative pathways in the development of CTE as well as clinical features including erythema, increased cancer risk, and growth abnormalities. Future studies should continue to explore innovations in this space, especially in regard to the use of artificial intelligence, including machine learning and deep learning, for the diagnosis and clinical management of rare diseases such as CTE.
PubMed: 37796556
DOI: 10.2196/48413 -
Aging Cell Oct 2023Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor...
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
Topics: Humans; Animals; Mice; Bloom Syndrome; Epigenesis, Genetic; Aging; Aging, Premature; Methylation; DNA Methylation
PubMed: 37594403
DOI: 10.1111/acel.13964