Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases

Perez, B.A.; Shutterly, A.; Chan, Y.K.; Byrne, B.J.; Corti, M.; Brain Sci. 2020, 10, 119; doi:10.3390/brainsci10020119 (registering DOI)

Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.

A Phase 2 Clinical Trial to Test the Safety and Efficacy of Etravirine in Friedreich Ataxia Patients (FAEST1)

ClinicalTrials.gov Identifier: NCT04273165. February 17, 2020, Sponsor: IRCCS Eugenio Medea, Collaborator: University of Rome Tor Vergata.

A drug repositioning effort provided evidence supporting the possible use of Etravirine, a drug approved for the treatment of HIV infections in patients starting from 2 years of age, as a treatment for FA. We found that Etravirine is able to increase Frataxin protein both in vitro - in cells derived from FA patients - and in vivo - in the heart and skeletal muscle of Frataxin-deficient YG8 mice. Because of these findings, and since Etravirine displays a generally favorable safety profile, we plan to launch an open-label, phase 2 clinical trial aimed at assessing the safety and efficacy of Etravirine in FA patients. We aim at recruiting 30 FA patients. 15 will be treated with Etravirine for 4 months at 200 mcg/day and 15 will be treated with Etravirine for 4 months at 400 mg/day. Efficacy primary endpoint will be represented changes in peak VO2 as measured by incremental cycle ergometer exercise test. Secondary endpoints will include maximal workload, SARA score, cardiac measures, Frataxin protein levels in peripheral blood mononuclear cells and molecular analysis of Frataxin mRNA translation efficiency. Complete sets of data will be collected 4 months before the start of the treatment (T -4), at the start (T0), after 2 months (T2), at the end of the treatment (T4) and 4 months after the termination of the treatment (T8).

Instrumented Data Exchange for Ataxia Study (IDEA)

ClinicalTrials.gov Identifier: NCT04268147. Sponsor: University of Chicago. Collaborators: Pfizer, Biogen, APDM Wearable Technologies.
This research study is testing body-worn sensors to measure movement during simple tests of coordination, in order to evaluate the progression and severity of ataxia.
Condition or disease: Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia Type 3, Spinocerebellar Ataxia Type 6, Friedreich Ataxia.

Loss of mitochondrial localization of human FANCG causes defective FANCJ helicase

Sudit S Mukhopadhyay, Jagadeesh Chandra Bose K, Bishwajit Singh Kapoor, Kamal Mandal, Subhrima Ghosh, Raveendra B Mokhamatam, Sunil K Manna; bioRxiv 2020.01.15.907303; doi:10.1101/2020.01.15.907303

Mitochondrial instability in the FANCGR22P cell causes the transcriptional down-regulation of mitochondrial iron-sulphur cluster biogenesis protein Frataxin (FXN) and resulting iron deficiency of FA protein FANCJ, an iron-sulphur containing helicase involved in DNA repair.


Despite of DNA repair ability the Fanconi anemia mutant protein FANCGR22P destabilizes mitochondria and leads to genomic instability via FANCJ helicase . Preprint from bioRxiv, 15 Jan 2020
DOI: 10.1101/2020.01.15.907303

NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis

Nady Braidy, Yue Liu; Experimental Gerontology, 2020, 110831, doi:10.1016/j.exger.2020.110831.

While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.

NOTE: NAD+ and Exercise in FA (ExRx in FA)

The Potential of the Novel NAD+ Supplementing Agent, SNH6, as a Therapeutic Strategy for the Treatment of Friedreich’s Ataxia

Shannon Chiang, Danuta S. Kalinowski, Mahendiran Dharmasivam, Nady Braidy, Des R. Richardson, Michael L.-H. Huang, Pharmacological Research, 2020, 104680, doi:10.1016/j.phrs.2020.104680

SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.

A Study to Assess Variation in Potential Biomarkers in Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT04255680, February 5, 2020
Intervention: Diagnostic Test: Buccal Swabs and Blood Draws
Sponsors: Chondrial Therapeutics, Inc.; Children's Hospital of Philadelphia. Enrolling by invitation

To test the variability of specific ribonucleic acid (RNA) and proteins as well as frataxin levels in samples of blood and buccal cells taken directly from patients with Friedreich's ataxia (FRDA) in order to confirm potential new biomarkers of disease in patients with FRDA.

DDIEM: Drug Database for Inborn Errors of Metabolism

Marwa Abdelhakim, Eunice McMurray, Ali Raza Syed, Senay Kafkas, Allan Anthony Kamau, Paul N Schofield, Robert Hoehndorf, bioRxiv 2020.01.08.897223; doi: doi:10.1101/2020.01.08.897223

We gathered data on therapeutic strategies for 299 diseases into the Drug Database for Inborn Errors of Metabolism (DDIEM), (FA included). Therapeutic approaches, including both successful and ineffective treatments, were manually classified by their mechanisms of action using a new ontology. Conclusions: We present a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes.

NfL and pNfH are increased in Friedreich’s ataxia

Stefanie Nicole Hayer, Inga Liepelt, Christian Barro, Carlo Wilke, Jens Kuhle, Peter Martus, Ludger Schöls, the EFACTS study group; J Neurol (2020). doi:10.1007/s00415-020-09722-6

Serum levels of NfL and pNfH are elevated in Friedreich’s ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up—a period relevant for biomarkers indicating treatment effects—we found NfL levels to be stable.

Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study

Rojas, P.; Ramírez, A.I.; Hoz, R.; Cadena, M.; Ferreras, A.; Monsalve, B.; Salobrar-García, E.; Muñoz-Blanco, J.L.; Urcelay-Segura, J.L.; Salazar, J.J.; Ramírez, J.M.; Diagnostics 2020, 10, 75. doi:10.3390/diagnostics10020075

The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.

Developing an objective evaluating system to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia

Giuseppe Arcuria, Christian Marcotulli, Raffaele Amuso, Giuliano Dattilo, Claudio Galasso, Francesco Pierelli, Carlo Casali; Neurol Sci (2020). doi:10.1007/s10072-020-04249-0

The purpose of our study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich’s ataxia. The APP, which we named “Twelve-Red-Squares App-Coo-Test” (12-RSACT), assesses the upper limb ataxia by measuring the test execution time. 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases.