Update on Novartis Gene Therapies Friedreich’s ataxia Program

Novartis Gene Therapies,  2022 . Novartis Gene Therapies had been developing a therapeutic approach for Friedreich’s ataxia. One candidate, OAV401, is an investigational AAV9-based gene therapy. The journey to bring new therapies from the lab to patients is complex and our team works with a sense of urgency, a need for flexibility and innovation, and an ability to accept challenges in a developing field of science. In this context, we have made the difficult decision to retire development of the OAV401 gene therapy program for Friedreich’s ataxia. However, we remain fully committed to innovative approaches, such as gene therapy, and are actively pursuing multiple pathways to harness this therapeutic platform. 

Unfortunately, the totality of the pre-clinical data for OAV401 does not support a path forward for this development candidate to human clinical trials. More specifically, data generated from a recent biodistribution study revealed that adequate gene expression was not achieved in the specific cells and tissues believed to be necessary for potential therapeutic benefit in patients with Friedreich’s ataxia. 

These data are complementary, not contradictory, to the research we have presented previously. The prior data demonstrated that OAV401 reached the brain. These more detailed findings, however, indicate that AAV9 does not distribute to the specific brain regions or cells that we believe would be necessary for therapeutic benefit in patients with Friedreich’s ataxia. 

We have made this data available to enhance the knowledge in the field of AAV9 gene therapy for neurologic conditions. The title of this paper is “Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques,” and it is posted on bioRxiv https://www.biorxiv.org/content/10.1101/2021.11.28.470258v1 ahead of peer-reviewed publication, expected later in 2022. 

We recognize this update is especially disappointing to the Friedreich’s ataxia patient community. We highly value our collaboration with the community and recognize that this partnership has significantly advanced the scientific understanding of the potential impact gene therapy could have for patients and families and has contributed to the development of potential clinical programs. We will continue to partner with the Friedreich’s ataxia community as we explore therapeutic options for this and other diseases.

Establishing and boosting communication in the European Reference Network for Rare Neurological Diseases (ERN-RND): the impact of offering free educational webinars

Alicia Brunelle Praschberger, Annemarie E. M. Post, Sanja Hermanns & Holm Graessner; Orphanet J Rare Dis 17, 89 (2022). doi:10.1186/s13023-022-02209-9

Offering a tangible product—such as the webinars presented in this report—to a specific target group (healthcare professionals) supported our communication strategy by driving traffic to ERN-RND communication channels. It has also successfully tackled ERN-RND’s general aim: by enabling the flow of knowledge on rare neurological and movement disorders to the medical community in hospitals treating patients with these rare and complex conditions, patients ultimately benefit from improved and faster diagnosis, care, and treatment. We aim to set up similar strategies to effectively reach other or the same target groups. For healthcare professionals, organising eConsultations via the Clinical Patient Management System or disseminating standards of care such as diagnostic and therapeutic algorithms as well as clinical practice guidelines might offer potential. For the patient community, organising customised and multilingual webinars could also work.

Larimar Therapeutics Inc. (NASDAQ: LRMR) Announces That The FDA Has Retained the Clinical Hold on CTI-1601

BioPharma Journal, March 2, 2022. Larimar Therapeutics Inc. has announced that it has received feedback from the US FDA about the clinical hold in its CTI-1601 program. 

The FDA indicated that it is retaining its clinical hold for now and that more data is required to lift the hold. Larimar is delving deeper into previously completed studies to see if more research is necessary. The company also plans to work with the FDA to figure out the best way to deliver this data. As part of its efforts to satisfy the agency’s request, Larimar is reevaluating recommendations on scheduling the scheduled Jive open-label expansion and pediatric multiple-ascending dosage clinical trials.

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Monfort B, Want K, Gervason S and D’Autréaux B.; Front. Neurosci. 16:838335. (2022) doi: 10.3389/fnins.2022.838335 

A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.

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.