Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia
- Celine J. Rocca1,
- Spencer M. Goodman1,
- Jennifer N. Dulin2,
- Joseph H. Haquang1,
- Ilya Gertsman1,
- Jordan Blondelle3,
- Janell L. M. Smith1,
- Charles J. Heyser2and
- Stephanie Cherqui1,*
Cell therapy for Friedreich’s ataxia
Friedreich’s ataxia (FRDA) is a lethal hereditary disease characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy and for which there is no treatment. Using a mouse model of FRDA, Rocca et al. show that wild-type hematopoietic stem and progenitor cell (HSPC) transplantation could lead to the rescue of the disease phenotype, including locomotor defects and muscle weakness. In addition, mitochondrial protein dysfunction was restored in the brain, skeletal muscle, and heart of the FRDA mice, potentially through transfer of mitochondrial proteins from HSPC-derived phagocytic cells to FRDA neurons and muscle myocytes.
Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. 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.
Reata Announces First Patient Enrolled in Part 2 of MOXIe Study of Omaveloxolone for the Treatment of Friedreich’s Ataxia
Incidence et caractéristiques de la scoliose neurologique dans l’ataxie de Friedreich à maturité osseuse
Incidence and description of scoliotic curves in Friedreich ataxia patients at skeletal maturity
L’ataxie de Friedreich (AF) est une maladie neurodégénérative spinocérébelleuse, débutant le plus souvent dans l’enfance. Elle est responsable d’une altération sévère de la marche mais également de déformations orthopédiques telles que la scoliose ou le pied creux neurologique. Cependant, l’évolution de cette déformation rachidienne au cours de la maladie a rarement été décrite. En effet, les caractéristiques radiologiques ainsi que l’incidence des types de courbures ne sont pas connues de même que l’échéance de l’indication chirurgicale. Actuellement, la chirurgie d’arthrodèse rachidienne est proposée lorsque les patients perdent leur capacité de marche par peur de les dégrader au plan fonctionnel. Le but de cette étude était de caractériser les courbures spécifiques de cette pathologie ainsi que le taux de chirurgie d’arthrodèse rachidienne dans une cohorte prospective de patients atteints d’AF en fin de croissance.
Matériel et méthodes
Dans cette étude prospective monocentrique, 68 patients avec une AF confirmée génétiquement ont été suivis entre 2008 et 2016. Une évaluation fonctionnelle de la marche et radiologique a été réalisée tous les ans. Ont été mesurés radiologiquement les angles de Cobb, les mesures segmentaires dans le plan sagittal et l’indice de Risser.
Au recul de 5 ± 2,3 ans, 51 patients présentaient une scoliose diagnostiquée à l’âge moyen de 12,7 ± 2,5 ans. Parmi cette cohorte, 27 patients (14H/13F) étaient à maturité osseuse (indice de Risser > 4). La courbure principale était thoracique dans 44 % des cas (12 patients) avec un angle de Cobb à 34° ± 15,5°, variant de 10° à 58°. Dans 30 % des cas (8 patients), il s’agissait d’une scoliose double majeure avec un angle de Cobb de 41° ± 11,4°, variant entre 23°et 61°. Le dernier groupe de patients présentait une scoliose lombaire avec un angle de Cobb à 27° ± 17,8°, variant entre 10°et 62°. Dans 33 % des cas, une hypercyphose (> 50°) a été retrouvée, principalement pour les scolioses lombaires. Neuf patients ont été opérés d’une arthrodèse rachidienne, dont 4 étaient encore marchants après l’arthrodèse.
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
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. He was diagnosed with Friedreich’s Ataxia at the age of 18 with genetic testing showing homozygous GAA expansions in the frataxin gene. His electrocardiogram was remarkable for inferolateral Q waves (PanelA). Cardiac magnetic resonance (CMR) cine imaging showed an ejection fraction of 45% with mild asymmetric septal hypertrophy (PanelsB and C, Supplementary material online, Videos S1 and S2). Late gadolinium enhancement imaging demonstrated septal mid-myocardial and patchy lateral hyperenhancement (PanelsD and E). Cardiac magnetic resonance feature-tracking demonstrated reduced global longitudinal strain (−11%) and diminished regional longitudinal strain particularly in…
Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias
Congratulations Dr. Guangbin Xia and Dr. S.H. Subramony on the publication of “Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias,” which was published in Tremor and Other Hyperkinetic Movements.
Background: Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known.
Methods: We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012.
Results: Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = –0.91, p < 0.001; SCA6, β = –1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = –1.53, p = 0.037) and ATXN3(β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = –0.40, p = 0.032).
Discussion: Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.
BioMarin Highlights Breadth of Innovative Development Pipeline at R&D Day on October 18th in New York
PRESS RELEASE PR Newswire
Oct. 18, 2017, 12:24 PM
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.
“We are pleased to share the progress of our development programs in therapies to treat rare genetic diseases; hemophilia A, PKU, achondroplasia and our next IND into Friedreich’s Ataxia,” said Hank Fuchs, M.D., President Worldwide Research and Development of BioMarin. “In the near term, we are expecting an FDA decision on pegvaliase to treat adults with uncontrolled PKU in the first half of next year, and we continue to be rapidly and decisively developing the potential first gene therapy for severe hemophilia A.”
BioMarin Selects BMN 290 for Friedreich’s Ataxia
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.
Public summary of opinion on orphan designation Recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein for the treatment of Friedreich’s ataxia
On 23 August 2017, orphan designation (EU/3/17/1906) was granted by the European Commission to Voisin Consulting S.A.R.L., France, for recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein (also known as AGIL-FA) for the treatment of Friedreich’s ataxia. What is Friedreich’s ataxia? Friedreich’s ataxia is an inherited disease that causes a range of symptoms that worsen over time, including difficulty walking, inability to co-ordinate movements, muscle weakness, speech problems, damage to the heart muscle, and diabetes. Patients with Friedreich’s ataxia do not have enough frataxin, a protein that regulates iron in mitochondria (energy-producing components of cells). As a result iron builds up within the cells, which in turns results in the production of toxic forms of oxygen that damage cells in the brain, the spinal cord and nerves, as well as in the heart and pancreas. Friedreich’s ataxia is a debilitating and life-threatening disease because of the worsening of symptoms over time. The disease is usually fatal in early adulthood. What is the estimated number of patients affected by the condition? At the time of designation, Friedreich’s ataxia affected approximately 0.5 in 10,000 people in the European Union (EU). This was equivalent to a total of around 26,000 people* , and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP). What treatments are available? At the time of designation, no satisfactory methods were authorised in the EU for the treatment of Friedreich’s ataxia. Different treatments were used to relieve the symptoms of the disease, such as * Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 28), Norway, Iceland and Liechtenstein. This represents a population of 515,700,000 (Eurostat 2017). Public summary of opinion on orphan designation EMA/498738/2017 Page 2/5 medicines for diabetes and heart problems. Patients were also offered walking aids to allow them to remain as independent as possible, and other devices to assist them with everyday tasks such as eating and taking care of themselves. Speech therapy and physiotherapy were also used. How is this medicine expected to work? This medicine consists of a virus that contains a gene that produces frataxin, the protein lacking in patients with Friedreich’s ataxia. When given directly into the brain of patients, the virus is expected to carry this gene into the brain cells. This would enable these cells to produce frataxin, thereby helping the cells to regulate iron normally, and is expected to improve the symptoms of the condition. The virus used in this medicine (adeno-associated virus) does not cause disease in humans. What is the stage of development of this medicine? The effects of the medicine have been evaluated in experimental models. At the time of submission of the application for orphan designation, no clinical trials with this medicine in patients with Friedreich’s ataxia had been started. At the time of submission, the medicine was not authorised anywhere in the EU for Friedreich’s ataxia. Orphan designation of the medicine had been granted in the United States for this condition. In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 July 2017 recommending the granting of this designation. __________________________ Opinions on orphan medicinal product designations are based on the following three criteria: • the seriousness of the condition; • the existence of alternative methods of diagnosis, prevention or treatment; • either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment. Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.
Voyager Therapeutics Announces New Data Presentations at the Congress of the European Society of Gene and Cell Therapy
New data with novel AAV gene therapy capsids demonstrate widespread gene transfer to the brain and spinal cord of non-human primates after a single intravenous administration
Additional studies at Voyager are underway in non-human primates with these novel capsids and other novel AAV vectors focusing on regions critical for the treatment of ALS, Friedreich’s ataxia, as well as brain regions and approaches for treating other areas for Parkinson’s disease and Huntington’s disease, and other severe neurological diseases
New data for Friedreich’s ataxia with a novel capsid demonstrate reversal of disease phenotype in a preclinical disease model
Voyager’s AAV gene therapy baculovirus/Sf9 system demonstrates increased yields and comparable quality compared with a mammalian-cell based manufacturing system
CAMBRIDGE, Mass., Oct. 17, 2017 (GLOBE NEWSWIRE) — Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases announced today multiple data presentations at the Congress of the European Society of Gene and Cell Therapy (ESGCT) taking place October 17-20, 2017, in Berlin, Germany. The data include an oral presentation related to recent results from Voyager’s ongoing Phase 1b trial of VY-AADC01 in advanced Parkinson’s disease, as well as six poster presentations related to Voyager’s novel adeno-associated virus (AAV) capsid optimization efforts, gene therapy manufacturing, and preclinical pipeline programs.
“A core competency of Voyager’s gene therapy platform is vector optimization and a critical component of this is optimizing and choosing the capsid, or outer shell of the gene therapy vector,” said Dinah Sah, Ph.D., Voyager’s chief scientific officer. “At this year’s ESGCT meeting, we describe exciting progress with novel AAV capsids that enhance the transfer of genes to the brain and spinal cord of non-human primates and in a preclinical model of Friedreich’s ataxia, representing unique opportunities for our current pipeline as well as for future potential programs. An additional core competency of Voyager is the production and manufacturing of AAV gene therapy vectors at scale, and at the meeting, we also describe the high yield and quality of AAV vectors produced with Voyager’s baculovirus/Sf9 manufacturing system.”
Mathematical modeling of Friedreich’s ataxia – a genetic neuro-muscular degenerative condition
SWASTI WAGH1 and D.K. WAGH2
1M.Sc. Applied Mathematics from G.S. Institute of Tech. and Sc., Indore, M.P., India
2Ph.D., Retired Prof. of Mathematics from G.S. Institute of Tech. and Sc. ,Indore, M.P., India
Corresponding Author Swasti Wagh :Email; firstname.lastname@example.org
Friedreich’s Ataxia, Stochastic matrix, Probability vector, Fixed point
In this paper we propose a mathematical model of Friedreich’s Ataxia (FA) – a genetic neuro-muscular degenerative condition which causes imbalance, in-coordination and jerky limb movements. These continue to increase till patient loses independence and becomes wheelchair bound. Currently Friedreich’s Ataxia (FA) is not considered an important health problem because of its relatively low prevalence in the general population. However with improvement in health care diagnosis and delivery provisions, more and more people with Friedreich’s Ataxia (FA) are being diagnosed and surviving. This means that its incidence and prevalence is bound to change. We have used a mathematical model to estimate generational increase in the number of patients and carriers with FA. The results portray a scary picture and hence demand measures to take it more seriously by health care providers.
Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone
Arnulf H. Koeppen, MD Alyssa B. Becker, BA Jiang Qian, MD, PhDBenjamin B. Gelman, MD, PhD Joseph E. Mazurkiewicz, PhD
Journal of Neuropathology & Experimental Neurology, Volume 76, Issue 11, 1 November 2017, Pages 969–977, https://doi.org/10.1093/jnen/nlx087
Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin. Normal DREZ showed short, sharply demarcated, dome-like extensions of CNS tissue into DR. The Schwann cell-related proteins formed tight caps around these domes. In FA, GFAP-, S100-, and vimentin-reactive CNS tissue extended across DREZ and into DR over much longer distances by breaching the CNS-PNS barrier. The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.
Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros; J. Cell. Mol. Med. Vol XX, No X, 2017 pp. 1-15 doi: 10.1111/jcmm.13365
In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia.
The Subclinical Cardiomyopathy of Friedreich’s Ataxia in a Pediatric Population
Identification of a subclinical cardiomyopathy in a pediatric patients with Friedreich’s ataxia (FA) has not been well-described.
We performed echocardiography (echo), cardiac magnetic resonance imaging (cMRI) and neurologic assessment in a cross-sectional analysis of 48 genetically-confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo and cMRI-determined left ventricular mass were indexed to height in g/m2.7 (LVMI). LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH) or eccentric hypertrophy based upon echo-determined relative LV wall thickness.
Echo LVMI exceeded age-based normal values in 85% of subjects and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E’: r= -0.65, p<0.001, S’: r=-0.46, p<0.001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r=0.55, p<0.001), a marker of elevated LV filling pressure. Similar associations were found with echo LV mass. Depressed LV relaxation and increased LV stiffness were observed in 88% and 71% of subjects despite a normal LV ejection fraction in almost all cases (mean = 60 + 7%). CR and CH were present in 40% and 44% of the study group though significant depressions of E’ and S’ were observed only in subjects with CH (p<0.005).
A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.