Gene therapy—from small beginnings to where we are now

J C Glorioso and N Lemoine; Gene Therapy (2017) 24, 495–496; doi:10.1038/gt.2017.23

While there have been many hurdles to overcome that relate to safety, immunity and manufacturing, still, the logic of this treatment modality remains intact and most of us in the field believe that it will take its place as a standard of care just as the use of monoclonal antibodies and pharmaceutical drugs of all types has become widely employed. This is especially true for diseases that are too complex to treat with single approaches, such as cancer.
GT is one of the most highly regulated therapeutic fields. There were numerous control bodies formed to understand the long-term impact of gene therapy and to consider the dangers of viral vector engineering and transfer to humans. While the risk inherent in GT success is quite high, the rewards are potentially enormous both from a commercial as well as human medicine point of view.
There are many fields such as organ transplantation technology that have taken many years to develop before they have become standard practice, and no doubt gene therapy will take a similar path. We predict that by mid-century, there will be many GT options for patients, and in combination with other treatment strategies, will move human medicine to reach heights that are currently unanticipated. The challenge will be how to deliver what are now expensive and difficult treatments to people worldwide who have less developed health care systems and wealth. Our sense is that as we create better treatment options, their costs will come down and rival immunization protocols.

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Celine J. Rocca, Spencer M. Goodman, Jennifer N. Dulin, Joseph H. Haquang, Ilya Gertsman, Jordan Blondelle, Janell L. M. Smith, Charles J. Heyser and Stephanie Cherqui; Science Translational Medicine 25 Oct 2017: Vol. 9, Issue 413, eaaj2347 DOI: 10.1126/scitranslmed.aaj2347

We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial?

Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB; Clin Rehabil. 2017 Oct 1:269215517736903. doi: 10.1177/0269215517736903.

Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich’s ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Reata Announces First Patient Enrolled in Part 2 of MOXIe Study of Omaveloxolone for the Treatment of Friedreich’s Ataxia

IRVING, Texas, Oct. 23, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (NASDAQ:RETA) (“Reata” or the “Company”) today announced the enrollment of the first patient in the pivotal Part 2 of the MOXIe trial to evaluate omaveloxolone in patients with Friedreich’s ataxia (FA).
Part 2 of the MOXIe trial is a double-blind, randomized, placebo-controlled, multi-center, international trial designed to evaluate the safety, tolerability, and efficacy of omaveloxolone in patients with FA. The trial will enroll approximately 100 FA patients randomized evenly to either 150 mg of omaveloxolone or placebo. The primary endpoint of the trial will be the change from baseline in the modified Friedreich’s Ataxia Rating Scale (mFARS) of omaveloxolone compared to placebo at 48 weeks. Additional endpoints will include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and Clinical Global Impression of Change. The U.S. Food and Drug Administration has confirmed that use of mFARS as the primary endpoint in Part 2 of the MOXIe trial can support approval of omaveloxolone in FA. Reata expects top-line data to be available in the second half of 2019.

Friedreich’s ataxia: clinical features, pathogenesis and management

A Cook, P Giunti; British Medical Bulletin,  2017, 1–12 doi:10.1093/bmb/ldx034

The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets.
The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants.
Management of Freidreich’s ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.

Incidence et caractéristiques de la scoliose neurologique dans l’ataxie de Friedreich à maturité osseuse

Jean Meyblum, Anne-Laure Simon, Christophe Vidal, Isabelle Husson, Bastien Roche, Brice Ilharreborde, Revue de Chirurgie Orthopédique et Traumatologique, Volume 103, Issue 7, Supplement, November 2017, Page S52, ISSN 1877-0517, doi:10.1016/j.rcot.2017.09.072.

L’incidence de la déformation scoliotique est élevée dans l’AF (74 % de la cohorte). Il n’existe pas de prévalence d’un type particulier de courbure. L’hypercyphose thoracique était fréquemment retrouvée sans être associée à un type de scoliose, témoignant du déséquilibre antérieur de la marche cérébelleuse. L’arthrodèse rachidienne n’a pas fait perdre la marche chez les patients marchant encore au moment de la chirurgie.

Cardiomyopathy in Friedreich’s Ataxia

Pablo Salazar, Raksha Indorkar, Michael Dietrich, Afshin Farzaneh-Far; European Heart Journal, , ehx607, doi:10.1093/eurheartj/ehx607

A 27-year old man with Friedreich’s Ataxia was referred for cardiac evaluation. He had no cardiac symptoms, and his physical exam was remarkable for an ataxic-gait and increased muscle tone.

Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich’s Ataxia

Petrillo, S.; Piermarini, E.; Pastore, A.; Vasco, G.; Schirinzi, T.; Carrozzo, R.; Bertini, E.; Piemonte, F.; Int. J. Mol. Sci. 2017, 18, 2173. doi:10.3390/ijms18102173

In FA, the dys-regulation of cellular antioxidant defenses, due to frataxin deficiency, exacerbates oxidative stress, thus the Nrf2 activation becomes more and more of an attractive strategy for the treatment of this disease.

Overall, our findings support Nrf2 as a therapeutic target for FA, and its induction as a promising approach to prevent or slow the pathological changes observed in this disease. Furthermore, the Nrf2 impairment mirrored at the systemic level in PBMCs of patients may help to open new perspectives for biomarker research in FA, potentially useful for monitoring clinical trials.

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV-1 vector

Maria Ventosa, Zetang Wu and Filip Lim; The Journal of Gene Medicine, Accepted manuscript online: 17 OCT 2017 08:40PM EST DOI: 10.1002/jgm.2993

With the aim of developing a gene therapy for FA neuropathology, here we describe the construction and preliminary characterization of a high capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B-FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1.

We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglion neurons with the H24B-FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B-FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.

Our results support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.

BioMarin Selects BMN 290 for Friedreich's Ataxia

SAN RAFAEL, Calif., Oct. 18, 2017 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) updated the investment community on the Company's development portfolio, which is focused on innovative therapies to treat rare and ultra-rare diseases.
BioMarin announced today that it has selected BMN 290, a selective chromatin modulation therapy, for the treatment of Friedreich's Ataxia (FA). FA is a rare autosomal recessive disorder with worldwide prevalence of approximately 15,000, which results in disabling neurologic and cardiac progressive decline. Currently there are no approved disease modifying therapies for FA. In preclinical models, BMN 290 increases frataxin expression in affected tissues more than two-fold. BMN 290 is a second generation compound derived from a compound acquired from Repligen that had human clinical data demonstrating increases in frataxin in FA patients. BMN 290 was selected for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. The company expects to submit the IND in 2H 2018.