SAN DIEGO--(BUSINESS WIRE)--Mar 20, 2020
Design Therapeutics announced today that it is launching to create and develop a new class of therapies for patients with serious degenerative disorders caused by nucleotide repeat expansions. The company has closed a $45 million Series A financing led by SR One, with participation from Cormorant Asset Management, Quan Capital and WestRiver Group, to advance its lead therapeutic candidate into clinical development for the treatment of Friedreich’s ataxia, and support advancement of its discovery programs for multiple other degenerative diseases, including fragile X syndrome and myotonic dystrophy.
Design Therapeutics has developed a novel program that unblocks transcription, thereby restoring the natural production and function of frataxin. With the use of proceeds from the Series A fundraising, Design Therapeutic intends to conduct IND-enabling studies and initiate clinical development for its program for Friedreich’s ataxia.
Saturday, March 21, 2020
Thursday, March 19, 2020
ENDOTHELIAL FRATAXIN DEFICIENCY DRIVES NUCLEAR REPLICATION STRESS-INDUCED SENESCENCE AND MITOCHONDRIAL DYSFUNCTION ACROSS MULTIPLE SUBTYPES OF PULMONARY HYPERTENSION
Miranda K. Culley, Jingsi Zhao, Ying Tang, Yi Yin Tai, Dror Perk, Vinny Negi, Yen-Chun Lai, Qiujun Yu, Adam Handen, Gil Speyer, Seungchan Kim, Taijyu Satoh, Michael Reynolds, Sruti Shiva, Annie Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Karen Norris, Aditi Gurkar, Mingxia Gu, Marlene Rabinovitch, Thomas Bertero and Stephen Chan; Journal of the American College of Cardiology, Volume 75, Issue 11 Supplement 1, March 2020 DOI: 10.1016/S0735-1097(20)34284-4
Endothelial DNA damage and metabolic dysfunction are linked to pulmonary hypertension (PH). Their joint regulation, control of cellular senescence, and relevance across PH subtypes are unknown. Mutations in the iron-sulfur (Fe-S) biogenesis gene frataxin (FXN) disrupt DNA integrity and metabolism, causing Friedreich’s ataxia (FRDA) and hypertrophic cardiomyopathy, often complicated by PH. Because Fe-S loss promotes PH, we hypothesized endothelial FXN deficiency induces genotoxic and metabolic dysregulation and predisposes to PH, particularly vascular remodeling due to ventricular stiffening.
FXN deficiency promotes replication stress-induced senescence and metabolic reprogramming across PH subtypes, including a predisposition to PH in FRDA. Our data endorse developing PH diagnostics and therapeutics related to Fe-S biology and genotoxic stress, namely for PH due to left heart disease.
Endothelial DNA damage and metabolic dysfunction are linked to pulmonary hypertension (PH). Their joint regulation, control of cellular senescence, and relevance across PH subtypes are unknown. Mutations in the iron-sulfur (Fe-S) biogenesis gene frataxin (FXN) disrupt DNA integrity and metabolism, causing Friedreich’s ataxia (FRDA) and hypertrophic cardiomyopathy, often complicated by PH. Because Fe-S loss promotes PH, we hypothesized endothelial FXN deficiency induces genotoxic and metabolic dysregulation and predisposes to PH, particularly vascular remodeling due to ventricular stiffening.
FXN deficiency promotes replication stress-induced senescence and metabolic reprogramming across PH subtypes, including a predisposition to PH in FRDA. Our data endorse developing PH diagnostics and therapeutics related to Fe-S biology and genotoxic stress, namely for PH due to left heart disease.
Tuesday, March 17, 2020
Enhanced production of herpes simplex virus 1 (HSV-1) amplicon vectors by gene modification and optimization of packaging cell growth medium
Iván Fernández-Frías, Sara Pérez-Luz, Javier Díaz-Nido, Molecular Therapy - Methods & Clinical Development, 2020, doi:10.1016/j.omtm.2020.03.005.
This work improved HSV-1 amplicons by genetic modification of the packaging cell line and optimization of the culture medium. A stably-transfected Vero 2-2 cell line overexpressing the anti-apoptotic Bcl-2 protein was generated, exhibiting an increased resistance to apoptosis, prolonged culture duration and a significant improvement in viral vector production. Additionally, supplementation of the growth medium with antioxidants, polyamines, amino acids and reduced glutathione further increased the yield of packaged amplicon vectors. With these modifications, HSV-1 amplicons could be isolated from culture supernatants instead of cell lysates, leading to vector preparations with higher titer and purity and paving the way for generation of stable cell lines that are capable of continuous herpesviral vector production.
This work improved HSV-1 amplicons by genetic modification of the packaging cell line and optimization of the culture medium. A stably-transfected Vero 2-2 cell line overexpressing the anti-apoptotic Bcl-2 protein was generated, exhibiting an increased resistance to apoptosis, prolonged culture duration and a significant improvement in viral vector production. Additionally, supplementation of the growth medium with antioxidants, polyamines, amino acids and reduced glutathione further increased the yield of packaged amplicon vectors. With these modifications, HSV-1 amplicons could be isolated from culture supernatants instead of cell lysates, leading to vector preparations with higher titer and purity and paving the way for generation of stable cell lines that are capable of continuous herpesviral vector production.
Friday, March 13, 2020
Advances in drug therapy for mitochondrial diseases.
Lufei Zhang, Zhaoyong Zhang, Aisha Khan, Hui Zheng, Chao Yuan, Haishan Jiang; Annals of Translational Medicine, 01 Jan 2020, 8(1):17
DOI: 10.21037/atm.2019.10.113
Mitochondrial diseases are a group of clinically and genetically heterogeneous disorders driven by oxidative phosphorylation dysfunction of the mitochondrial respiratory chain which due to pathogenic mutations of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Recent progress in molecular genetics and biochemical methodologies has provided a better understanding of the etiology and pathogenesis of mitochondrial diseases, and this has expanded the clinical spectrum of this conditions. But the treatment of mitochondrial diseases is largely symptomatic and thus does not significantly change the course of the disease. Few clinical trials have led to the design of drugs aiming at enhancing mitochondrial function or reversing the consequences of mitochondrial dysfunction which are now used in the clinical treatment of mitochondrial diseases. Several other drugs are currently being evaluated for clinical management of patients with mitochondrial diseases. In this review, the current status of treatments for mitochondrial diseases is described systematically, and newer potential treatment strategies for mitochondrial diseases are also discussed.
DOI: 10.21037/atm.2019.10.113
Mitochondrial diseases are a group of clinically and genetically heterogeneous disorders driven by oxidative phosphorylation dysfunction of the mitochondrial respiratory chain which due to pathogenic mutations of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Recent progress in molecular genetics and biochemical methodologies has provided a better understanding of the etiology and pathogenesis of mitochondrial diseases, and this has expanded the clinical spectrum of this conditions. But the treatment of mitochondrial diseases is largely symptomatic and thus does not significantly change the course of the disease. Few clinical trials have led to the design of drugs aiming at enhancing mitochondrial function or reversing the consequences of mitochondrial dysfunction which are now used in the clinical treatment of mitochondrial diseases. Several other drugs are currently being evaluated for clinical management of patients with mitochondrial diseases. In this review, the current status of treatments for mitochondrial diseases is described systematically, and newer potential treatment strategies for mitochondrial diseases are also discussed.
Tuesday, March 10, 2020
Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis
Nunziata Maio, Tracey A. Rouault; Trends in Biochemical Sciences, 2020, doi:10.1016/j.tibs.2020.02.001.
Structural determinations of the architecture of the initial ISC biogenesis complex, comprising NFS1, ISD11, ACP, ISCU, and FXN, have shed light on the interactions that govern de novo ISC assembly.
Structural determinations of the architecture of the initial ISC biogenesis complex, comprising NFS1, ISD11, ACP, ISCU, and FXN, have shed light on the interactions that govern de novo ISC assembly.
Sunday, March 8, 2020
The Assessment of Upper Limb Functionality in Friedreich Ataxia via Self-Feeding Activity
K. D. Nguyen, L. A. Corben, P. N. Pathirana, M. K. Horne, M. B. Delatycki and D. J. Szmulewicz, IEEE Transactions on Neural Systems and Rehabilitation Engineering. DOI: 10.1109/TNSRE.2020.2977354
The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34±14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.
The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34±14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.
Thursday, March 5, 2020
Polyunsaturated Fatty Acid Deuteration against Neurodegeneration
Mikhail S. Shchepinov, Trends in Pharmacological Sciences, 2020, doi:10.1016/j.tips.2020.01.010.
Regioselective deuteration that reinforces oxidation-prone, bis-allylic sites of PUFAs is a novel, nonantioxidant treatment modality that dramatically reduces LPO, potentially mitigating numerous diseases through preservation of membrane properties and amelioration of oxidative stress. Animal disease models and several ongoing human clinical trials highlight the potential of the deuterated-PUFA (D-PUFA) drug candidates currently in development.
Regioselective deuteration that reinforces oxidation-prone, bis-allylic sites of PUFAs is a novel, nonantioxidant treatment modality that dramatically reduces LPO, potentially mitigating numerous diseases through preservation of membrane properties and amelioration of oxidative stress. Animal disease models and several ongoing human clinical trials highlight the potential of the deuterated-PUFA (D-PUFA) drug candidates currently in development.
Wednesday, March 4, 2020
Identification of Frataxin as a regulator of ferroptosis
Jing Du, Yi Zhou, Yanchun Li, Jun Xia, Yongjian Chen, Sufeng Chen, Xin Wang, Weidong Sun, Tongtong Wang, Xueying Ren, Xu Wang, Yihan An, Kang Lu, Wanye Hu, Siyuan Huang, Jianghui Li, Xiangmin Tong, Ying Wang; Redox Biology, 2020, 101483, doi:10.1016/j.redox.2020.101483.
This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
Tuesday, March 3, 2020
An Overview of the Current State and the Future of Ataxia Treatments
Kimberly Tsu Kwei, Sheng-Han Kuo; Neurologic Clinics, 2020, doi:10.1016/j.ncl.2020.01.008.
Keywords: Cerebellum; Ataxia; Multiple system atrophy; Spinocerebellar ataxia; Friedreich ataxia; Ataxia treatment
Keywords: Cerebellum; Ataxia; Multiple system atrophy; Spinocerebellar ataxia; Friedreich ataxia; Ataxia treatment
Sunday, March 1, 2020
Epigenetic regulation of clinical manifestations of Friedreich's disease
Nuzhny EP, Abramycheva NY, Nikolaeva NS, Ershova MV, Klyushnikov SA, Illarioshkin SN, Fedotova EY.; Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(1):20-26. doi: 10.17116/jnevro202012001120. [Article in Russian; Abstract available in Russian from the publisher]
Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed.
Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed.
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