Reply to Townes-Anderson: RPE65 gene therapy does not alter the natural history of retinal degeneration

BackgroundDefects in retinol dehydrogenase 12 (RDH12) account for 3.4%–10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration.MethodsA retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.Results57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.ConclusionsThis study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

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Changing the Natural History of Fanconi Anemia Complementation Group-À with Gene Therapy: Early Results of U.S. Phase I Study of Lentiviral-Mediated Ex-Vivo FANCA Gene Insertion in Human Stem and Progenitor Cells

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2019.12.106 ◽

2020 ◽

Vol 26 (3) ◽

pp. S39-S40

Author(s):

Agnieszka Czechowicz ◽

Paula Rio ◽

Juan E. Bueren ◽

Brian Beard ◽

Eileen Nicoletti ◽

...

Keyword(s):

Gene Therapy ◽

Natural History ◽

Phase I Study ◽

Ex Vivo ◽

Complementation Group ◽

Gene Insertion ◽

Early Results ◽

Stem And Progenitor Cells ◽

History Of ◽

Group A

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First-in-human AAV Gene Therapy for Tay-Sachs Disease

10.21203/rs.3.rs-195847/v1 ◽

2021 ◽

Author(s):

Miguel Sena-Esteves ◽

Terence Flotte ◽

Oguz Cataltepe ◽

Ajit Puri ◽

Ana Rita Batista ◽

...

Keyword(s):

Gene Therapy ◽

Natural History ◽

Post Injection ◽

Proof Of Concept ◽

Safety And Efficacy ◽

Tay Sachs Disease ◽

Younger Patient ◽

Hexosaminidase A ◽

History Of ◽

Preclinical Work

Abstract Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225). Case TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab. Injection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age). Administration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy.

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How is the moral stance related to the intentional stance and group thinking?

Behavioral and Brain Sciences ◽

10.1017/s0140525x19002413 ◽

2020 ◽

Vol 43 ◽

Author(s):

Hannes Rakoczy

Keyword(s):

Natural History ◽

Social Cognitive ◽

Intentional Stance ◽

Cognitive Capacities ◽

Shared Intentionality ◽

History Of ◽

Group Thinking ◽

Moral Stance

Abstract The natural history of our moral stance told here in this commentary reveals the close nexus of morality and basic social-cognitive capacities. Big mysteries about morality thus transform into smaller and more manageable ones. Here, I raise questions regarding the conceptual, ontogenetic, and evolutionary relations of the moral stance to the intentional and group stances and to shared intentionality.

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