Design Therapeutics Announces FDA Clearance of Investigational New Drug Application for First GeneTAC™ Molecule for Friedreich Ataxia

CARLSBAD, Calif., Feb. 28, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a biotechnology company developing treatments for degenerative genetic disorders, today announced that its Investigational New Drug Application (IND) for its lead candidate, DT-216, for the treatment of Friedreich ataxia (FA), was cleared by the U.S. Food and Drug Administration (FDA). The company is preparing to initiate a Phase 1 clinical trial of DT-216 to assess the safety, tolerability, pharmacokinetics, and frataxin (FXN) levels in patients with FA. Study enrollment is expected to begin in the coming weeks.

Accurate and simple FXN-GAA repeats (Friedreich ataxia loci) estimation by long read targeted sequencing.

Pooja Sharma, Bharathram Uppilli, Istaq Ahmad, Shweta Sahni, Mohammed Faruq; bioRxiv 2022.02.24.481841; doi:10.1101/2022.02.24.481841 

 We describe for the first time a method of long read sequencing wherein we utilized approach of long range targeted amplification of FXN-GAA repeats and sequencing on oxford MinION platform. We were able to achieve the successful amplification of GAA repeats ranging from 180-1200 at 250x coverage. The total throughput achievable for 96 samples can be less than 24 hours on one flow cell as per our protocol and is scale-able and deploy-able at clinical day to sequencing.

Mitochondrial De Novo Assembly of Iron–Sulfur Clusters in Mammals: Complex Matters in a Complex That Matters

Citation: Perfitt, T.L.; Martelli, A.; Inorganics 2022, 10, 31. doi:10.3390/inorganics10030031

Recently obtained structural and biochemical data have painted a clearer picture of the mitochondrial Fe–S core complex, its protein interactions, and the steps involved in generating Fe–S. They open a venue for new and exciting research to address unanswered questions. For instance, what is the source of iron in the process? How, where, and when does FDX2 bind to the core complex during Fe–S assembly? What is the nature of the Fe–S intermediate on ISCU2 before its dimerization? How does dimerization of ISCU2 occur? Additionally, the intriguing relationship between ACP, the mitochondrial synthesis of long acyl chain and the Fe–S core complex function deserves particular attention. Importantly, the elucidation of these mechanisms and functions will require complementary experiments to ensure the physiological relevance of in vitro observations.

Selected Histone Deacetylase Inhibitors Reverse the Frataxin Transcriptional Defect in a Novel Friedreich’s Ataxia Induced Pluripotent Stem Cell-Derived Neuronal Reporter System

Schreiber Anna M., Li Yanjie, Chen Yi-Hsien, Napierala Jill S., Napierala Marek; Front. Neurosci., 16, 23 February 2022 doi:10.3389/fnins.2022.836476 

 Only selected histone deacetylase inhibitors were capable of partial reactivation of FXN expression. This endogenous, FRDA iPSC-derived reporter can be utilized for high-throughput campaigns performed in cells most relevant to disease pathology in search of FXN transcription activators.

Jupiter Neurosciences, Inc. Announces Completion of Phase I Safety Trial with Enhanced Resveratrol Product, JOTROL™ Jupiter Neurosciences logo

JUPITER, Fla. and BOSTON, Feb. 23, 2022 /PRNewswire/ -- Jupiter Neurosciences, Inc. ("Jupiter" or the "Company"), today announced the completion of its Phase I clinical trial with its proprietary JOTROL™, an enhanced formulation of resveratrol with increased bioavailability. In this first-in-man trial, JOTROL™ was administered in ascending doses in normal healthy volunteers to assess safety, tolerability, and pharmacokinetics. JOTROL™ was determined to be safe and well tolerated at all dose levels administered, with the data safety monitoring board (DSMB) reporting no serious adverse events (SAEs). Additionally, JOTROLTM demonstrated blood plasma levels 8-10-fold higher than naïve resveratrol administered in historical clinical trials, meeting performance objectives. 

"These data are exciting to report as we continue the advancement of our proprietary JOTROL™," stated Marshall Hayward, Ph.D., co-founder and CSO of Jupiter Neurosciences. "We believe that resveratrol has strong therapeutic potential but also shows poor bioavailability, which is treatment limiting. Optimizing the natural therapeutic power of resveratrol has been a focus of study for decades, and our ability to improve the formulation to produce such efficient adsorption is a breakthrough for the Company."

Downregulation of Three Immune-Specific Core Genes and the Regulatory Pathways in Children and Adult Friedreich's Ataxia: A Comprehensive Analysis Based on Microarray

Liu, Lichun; Lai, Yongxing; Zhan, Zhidong; Fu, Qingxian; Jiang, Yuelian (2022). Front. Neurol., 14 February 2022, doi:10.3389/fneur.2021.816393 

Downregulation of three immune-specific hub genes, CD28, FAS, and IFIT5, may be associated with the progression of child and adult FRDA. Furthermore, NEAT1-hsa-miR-24-3p-CD28 may be the potential RNA regulatory pathway related to the pathogenesis of child and adult FRDA.

Selection of Synthetic Proteins to Modulate the Human Frataxin Function

Pignataro MF, Herrera MG, Fernández NB, Aran M, Bataglini F, Santos J; Preprint from bioRxiv, 12 Feb 2022, DOI: 10.1101/2022.02.11.480108 

 We focused on Affi_224, one of the proteins that we were able to select after five selection rounds. We have studied the interaction between both proteins and discussed some applications of this specific molecular tutor, concerning the modulation of supercomplex activity. Affi_224 and frataxin showed a KD value in the nanomolar range, as judged by surface plasmon resonance analysis. Most likely, it binds to the frataxin acidic ridge, as suggested by the analysis of chemical shift perturbations (NMR) and computational simulations. Affi_224 was able to increase Cys NFS1 desulfurase activation exerted by the FRDA frataxin variant G130V. Our results suggest quaternary addition may be a new tool to modulate frataxin function in vivo. Nevertheless, more functional experiments under physiological conditions should be carried out to evaluate Affi_224 effectiveness in FRDA cell models.

LEXEO Therapeutics Announces FDA Clearance of Investigational New Drug Application for LX2006, an AAV-based Gene Therapy Candidate for Friedreich’s Ataxia Cardiomyopathy

NEW YORK, Feb. 16, 2022 (GLOBE NEWSWIRE) -- LEXEO Therapeutics.

LEXEO today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for LX2006. LX2006 is an AAV-based gene therapy candidate designed to intravenously deliver a functional frataxin gene, for the treatment of Friedreich’s ataxia cardiomyopathy (FA cardiomyopathy). LEXEO plans to initiate this open-label, dose-escalation Phase 1/2 clinical trial of LX2006 in patients with FA cardiomyopathy in the middle of 2022. 

The Phase 1/2 study is a 52-week, dose-ascending, open-label trial of LX2006 in patients who have FA cardiomyopathy. LX2006 will be administered as a one-time intravenous infusion to patients in two ascending-dose cohorts of five patients each.

FDA Maintains Clinical Hold on Larimar’s Friedreich’s Ataxia Study

Global Genes. February 15, 2022. Larimar Therapeutics, a company focused on developing treatments for complex rare diseases, said that the U.S. Food and Drug Administration is maintaining the clinical hold on Larimar’s CTI-1601 program for the treatment of Friedreich’s ataxia.

Retrotope announces Phase 2/3 trial of RT001 in FA did not successfully meet its endpoints

Friedreich's Ataxia Research Alliance, 14 February 2022.  FARA has been notified by Retrotope that the recently completed Phase 2/3 trial of RT001 in FA did not successfully meet its endpoints.

In October 2019, Retrotope launched a Phase 2/3 trial in FA, A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects with FA. This was a double-blind, placebo-controlled trial to study the impact of RT001 on neurological and cardiac symptoms and evaluate safety over 11 months of treatment. The trial enrolled 65 individuals who are ages 12-50 yrs and the primary outcome measure was peak workload change from baseline to 11 months using cardiopulmonary exercise testing (CPET). There were also secondary outcome measures to further assess neurological outcomes and fatigue.

The sponsor, Retrotope, has informed FARA and the trial investigators that the drug failed to reach its primary and key secondary endpoints in this study. Unfortunately, they report that there was no improvement in exercise measures or neurological outcomes assessed in the study. Even though the drug failed to show positive effects, we may learn important information from the trial. Therefore, the site investigators, along with Retrotope, are in the process of reviewing the detailed results over the next few weeks to see if there are insights from the trial that will be important to share with the FA community. We are disappointed in the results of the trial, however negative results are valuable and inform our future progress for other treatments in our pipeline. We are appreciative to Retrotope for bringing a potential therapy for FA to clinical trials. We want to thank and acknowledge all of the individuals who volunteered for the trial of RT001 along with the site investigators and coordinators who performed the trial.

Larimar Therapeutics Provides Update on CTI-1601 Clinical Program

BALA CYNWYD, Pa., Feb. 14, 2022 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) FDA stated it is maintaining its clinical hold at this time and that additional data is needed to resolve the clinical hold. Larimar is further analyzing previously completed studies, and is evaluating if additional studies are warranted. The Company also intends to engage FDA to determine how best to provide these data. Larimar is currently reassessing guidance on the timing of the planned Jive open-label extension and pediatric multiple-ascending dose clinical trials as it works to meet the agency’s request.

SARS-CoV-2 attacks the weakest point - COVID-19 course in a pediatric patient with Friedreich's ataxia

Kamil Faltin, Zuzanna Lewandowska, Paweł Małecki, Krzysztof Czyż, Emilia Szafran, Agnieszka Kowalska-Tupko, Anna Mania, Katarzyna Mazur-Melewska, Katarzyna Jończyk-Potoczna, Waldemar Bobkowski, Magdalena Figlerowicz; International Journal of Infectious Diseases, 2022, doi:10.1016/j.ijid.2022.02.021. 

COVID-19 pandemic is the biggest epidemiological problem of the 21st century. The severe course of SARS-CoV-2 infection in children is rare. Sometimes, especially in patients with chronic disease, COVID-19 may be insidious and life-threatening. This article presents the course of COVID-19 in a 17-year-old boy with Friedreich's ataxia-induced hypertrophic cardiomyopathy. Despite that the main symptoms of COVID-19 (i.e., fever, cough) were moderate at the beginning of the illness, the patient condition deteriorated rapidly due to cardiac problems, atrial fibrillation, and heart failure. He required antiarrhythmic treatment and pharmacological and electrical cardioversion. Moreover, because of pneumonia requiring supplemental oxygen, remdesivir and convalescent plasma therapy were utilized in this patient. For the patient recovery, the administration of the antiviral treatment was crucial.

R. Protein Mutations and Stability, a Link with Disease: The Case Study of Frataxin

Puglisi, Biomedicines 2022, 10, 425. doi:10.3390/biomedicines10020425

Protein mutations may lead to pathologies by causing protein misfunction or propensity to degradation. For this reason, several studies have been performed over the years to determine the capability of proteins to retain their native conformation under stress condition as well as factors to explain protein stabilization and the mechanisms behind unfolding. In this review, we explore the paradigmatic example of frataxin, an iron binding protein involved in Fe–S cluster biogenesis, and whose impairment causes a neurodegenerative disease called Friedreich’s Ataxia (FRDA). We summarize what is known about most common point mutations identified so far in heterozygous FRDA patients, their effects on frataxin structure and function and the consequences of its binding with partners.

In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency

Claudia Huichalaf, Tyler L. Perfitt, Anna Kuperman, Renea Gooch, Ramesh C. Kovi, Karrie A. Brenneman, Xian Chen, Dinesh Hirenallur-Shanthappa, Tiffany Ma, Basel T. Assaf, Ingrid Pardo, Tania Franks, Laura Monarski, Ting-Wen Cheng, Kevin Le, Chunyan Su, Suryanarayan Somanathan, Laurence O. Whiteley, Christine Bulawa, Marko J. Pregel, Alain Martelli; Molecular Therapy - Methods & Clinical Development, 2022, doi:10.1016/j.omtm.2022.02.002. 

At the lowest tested dose, we observed moderate liver toxicity that was accompanied by progressive loss of transgene expression and liver regeneration. Together, our data provide insights into the toxicity of frataxin overexpression that should be considered in the development of a gene therapy approach for Friedreich’s ataxia.

Patients’ access to rare neuromuscular disease therapies varies across US private insurers

Nikoletta M. Margaretos, Komal Bawa, Natalie J. Engmann & James D. Chambers; Orphanet J Rare Dis 17, 36 (2022). doi:10.1186/s13023-022-02182-3

The high cost of providing coverage for rare disease therapies remains a key challenge for health insurers. This challenge will increase as regulatory agencies continue to approve increasingly large numbers of rare disease therapies and healthcare payers have to balance providing access with budget constraints. The evaluated set of large US private insurers tended to apply coverage restrictions beyond the FDA label indication in their coverage policies for a set of rare NMD DMTs. Plans rarely applied the same criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies, which may have important consequences for patients who move from one plan to another.