Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions

Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions; Ashraf Mohammed, M. Brett Waddell, Ieva Sutkeviciute, Adithi Danda, Steven J. Philips, Walter Lang, P. Jake Slavish, Sandra J. Kietlinska, Mangesh Kaulage, Das Sourav, and Aseem Z. Ansari; J. Am. Chem. Soc. 2023, XXXX, XXX, XXX-XXX; Publication Date:November 3, 2023; doi:10.1021/jacs.3c06297 

SynTEF1, a prototype synthetic genome reader/regulator (SynGR), was designed to target GAA triplet repeats and restore the expression of frataxin (FXN) in Friedreich’s ataxia patients. 

SynGRs as chemical probes provide unique insights into the molecular recognition principles utilized by natural factors to precisely regulate gene expression, and they guide the design of more sophisticated synthetic gene regulators with greater therapeutic potential.

Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients

Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients. Berta Alemany-Perna, Jordi Tamarit, Daniel Lopez Dominguez, Anna Quiroga-Varela, Miguel Merchan-Ruiz, Lluis Ramio Torrenta, David Genis Batlle, Joaquim Ros; medRxiv 2023.10.28.23297713; doi:10.1101/2023.10.28.23297713 

The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. Conclusion: Calcitriol dosage used (0.25mcg/24h) is safe for FRDA patients and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits.

The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure

Cantrell AC, Zeng H, Chen JX. The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure. J Cardiovasc Pharmacol. 2023 Oct 10. doi: 10.1097/FJC.0000000000001496. Epub ahead of print. PMID: 37816193. 

We provide a brief overview of the potential roles of SIRT3 in mitochondrial iron homeostasis, as well as its contribution to the mitochondrial cardiomyopathy of Friedreich's ataxia (FRDA) and diabetic cardiomyopathy (DCM).

End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases

Anne-Claire D, Coarelli G, Heinzmann A, Verdon B, Manuella L, Petit E, Pierron L, Levy-Soussan M, Durr A, Gargiulo M, Ewenczyk C. End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases. Neurol Clin Pract. 2023 Dec;13(6):e200199. doi: 10.1212/CPJ.0000000000200199. Epub 2023 Oct 16. PMID: 37854177; PMCID: PMC10581072. DIRAGENE is an observational, cross-sectional, mixed-methods study with a patient-centered component and a primary caregiver-centered component. Observations include disease severity, psychosocial, and emotional scales; in-house questionnaires; and semidirected interviews.

 

Rehabilitation Program on Genetic and Degenerative Ataxia (RAPP)

ClinicalTrials.gov ID NCT06089863. Sponsor Hospices Civils de Lyon.

The present protocol aimed at evaluating the Rehabilitation Program in collaboration with partner patient on the symptom intensity, activity and quality of life on genetic and degenerative ataxia. 

This PAMPERO program's effect will be assessed by comparing the difference of Intensity of symptom measured by to Scale for the Assessment and Rating of Ataxia (SARA) at inclusion and 3 months after the end of rehabilitation.

Detection of alternative DNA structures and its implications for human disease

Matos-Rodrigues G, Hisey JA, Nussenzweig A, Mirkin SM. Detection of alternative DNA structures and its implications for human disease. Molecular Cell. 2023 Oct;83(20):3622-3641. DOI: 10.1016/j.molcel.2023.08.018. PMID: 37863029. 

 The most well-known REDs include Huntington’s disease (HD), fragile X syndrome (FXS), and Friedreich’s ataxia (FRDA), which are caused by the expansion of (CAG)n, (CGG)n, and (GAA)n repeats, respectively. Thus, DNA sequences prone to formalternative DNA structures are highly frequent in the human genome and associated with several human diseases.

Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis

Gavriilaki M, Chatzikyriakou E, Moschou M, Arnaoutoglou M, Sakellari I, Kimiskidis VK. Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis. Cerebellum. 2023 Oct 27. doi: 10.1007/s12311-023-01621-6. Epub ahead of print. PMID: 37889470.

 Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified.

Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs

Sylvia Boesch & Elisabetta Indelicato (2023) Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2023.2276758 

 Generally, therapeutic approaches in FA are divided in two categories. One group of therapeutics (including gene therapy) aims at increasing/restoring frataxin levels. The second group encompasses those approaches aiming at reversing the consequence of frataxin loss at a tissue level, for instance mitochondrial failure. The first class of therapeutics may appear the most appealing as they intervene very early in the pathogenic cascade and may be potentially curative. Currently, various gene therapy and genome editing strategies are explored in FA. The likelihood of toxicity issues when overexpressing frataxin and the need for a delivery system with widespread distribution and low immunogenicity are among the hurdles to be addressed. Beyond these biological hinders, it is however not clear when such treatments should be administered to guarantee a reversal or at least a substantial improvement of the clinical phenotype. The presence of a developmental aspect as well as of a neurodegenerative kind of progression after onset suggest that the benefit of gene therapy/genome editing would be limited if applied beyond an early clinical phase.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Teerapat Rojsajjakul, Juliette J. Hordeaux, Gourav R. Choudhury, Christian J. Hinderer, Clementina Mesaros, James M. Wilson & Ian A. Blair. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy. Commun Biol 6, 1093 (2023). doi:10.1038/s42003-023-05472-z 

Increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. 

The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

PTC Therapeutics Provides Corporate Update and Reports Third Quarter Financial Results

NEWS PROVIDED BY PTC Therapeutics, Inc. , 26 Oct, 2023 

PTC had a type C written-response-only meeting with FDA for vatiquinone for Friedreich ataxia to determine whether the data from the MOVE-FA study would be sufficient to support an NDA for accelerated approval. In their written response, the FDA stated that while they see the value of upright stability as a clinically meaningful endpoint, they believed a confirmatory study would likely be needed to support NDA submission. PTC has requested a follow-up live meeting to address the issues raised by the FDA. PTC is participating in a scientific advice procedure with the EMA to determine if the MOVE-FA data could support a conditional marketing authorization application in the EEA. PTC expects to have the outcome of this procedure in the first quarter of 2024.