GenSight Biologics Announces the Publication in Communications Biology of the Proof-of-Concept for GS030-Drug Product in Non‑Human Primates
GenSight Biologics announced that the journal Communications Biology has published results from the study of GS030-Drug Product (GS030-DP) in non-human primates (NHP).
The paper,* published in the January issue under the title “Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates,” is the first peer-reviewed article constituting a proof-of-concept for retinal ganglion cell (RGC) activation following optogenetic gene therapy with GS030-DP (rAAV2.7m8-ChrimsonR-tdT) in non-human primates. Specifically, the spatiotemporal activation of RGCs allowed for pattern discrimination leading to an estimated Snellen visual acuity of 20/249, superior to the level of legal blindness.
“We are proud to have these results, which have been used to support the IND approval of our phase 1/2 clinical trial PIONEER with GS030, published in Communications Biology,” Bernard Gilly, Co-founder and Chief Executive Officer of GenSight, said in a company news release. “This phase 1/2 clinical trial is currently recruiting retinitis pigmentosa patients with bare light perception and its objective is to demonstrate that NHP observations translate into useful visual restoration in these patients”.
GS030-DP (rAAV2.7m8-ChrimsonR-tdT) is an optimized viral vector expressing the light-sensitive opsin ChrimsonR. When activated by amber light, ChrimsonR renders its host cell photosensitive, a function lost in retinal diseases causing the degeneration of photoreceptors. Optogenetics combine the cellular expression of light-sensitive opsins with fine-tuned light stimulation generated by a wearable optronic visual stimulation device (GS030-MD).
Preclinical studies generated key findings that supported the initiation of the first-in-human phase 1/2 clinical trial PIONEER evaluating the safety and tolerability of the GS030 combined therapy (GS030-DP + GS030-MD) in patients with late-stage retinitis pigmentosa.
“This preclinical study represents an important milestone towards the clinical validation of this approach to restore some vision in blinding retinal conditions. This journey that started more than a decade ago with the collaboration between my team at Institut de la Vision in Parisa and Pr. Botond Roska, has also benefited from scientific synergies with the team of Ed Boyden at the MIT,” said José-Alain Sahel, MD, co-founder of GenSight and of the Institut de la Vision, Director of the IHU FOReSIGHT and Chairman of the Department of Ophthalmology at University of Pittsburgh School of Medicine. “We expect that the results of the clinical trial PIONEER will indeed confirm the potency of the approach in the interest of patients.”
Expression of ChrimsonR-tdT in the retina of non-human primates was safe and well tolerated
The intravitreal injection of rAAV2.7m8-ChrimsonR-tdT and the expression of ChrimsonR-tdT in the retina did not induce any significant immune reaction or intraocular inflammation. Under ambient lighting, no photophobia or vision‑related changes in behavior was noted in any of the animals injected with rAAV2.7m8-ChrimsonR-tdT. Of note, the wavelength of amber light needed to activate ChrimsonR is much safer than that of highly phototoxic blue-shifted lights.2
The AAV2.7m8 vector showed high transduction efficiency in retinal ganglion cells (RGCs)
The modified viral vector AAV2.7m8 was generated using in vivo–directed evolution and selected for its ability to efficiently transduce retina cells when injected in the vitreous.1 The article authored by Gauvain et al. showed that, in macaques injected intravitreally, AAV2.7m8 transduced RGCs more efficiently than the wild-type AAV2 vector. A strong cellular expression of ChrimsonR-tdT was observed in the perifovea, where RGCs are most concentrated. Interestingly, the fluorescent marker protein td-Tomato fused to ChrimsonR seemed to increase the expression of functional opsin.
The therapeutic dose of rAAV2.7m8-ChrimsonR-tdT was defined as 5 × 1011 vg/eye, which allowed for greater light sensitivity and higher cellular expression in a wider area of the retina.
ChrimsonR-tdT generated a photocurrent with high temporal and spatial resolution
In functional assays (256-mutlielectrode arrays), the RGCs expressing ChrimsonR-tdT were only activated by amber light at a minimal intensity of 1015 photons cm−2 s−1 and did not show any response to ambient light.
The ex vivo retinal stimulation assays also showed that the electrophysiologic response of RGCs expressing ChrimsonR precisely followed the duration and frequency of the light pulses used to activate the opsin. Moreover, localized stimulation of RGCs induced a response coherent with the size and position of the light pulses.
Optogenetic stimulation of RGCs expressing ChrimsonR-tdT can support restoration of visual acuity
The electrophysiological activity of RGCs expressing ChrimsonR-tdT was consistent with the direction and speed of a moving stimulus. Furthermore, the spatiotemporal activation of treated retinas was specific to the shape of the moving symbols presented (square, circle, cross of different sizes), indicating the ability to discriminate between patterns. This level of pattern discrimination corresponded to a Snellen visual acuity of 20/249 (1.1 LogMAR), a level above the threshold of blindness (20/400) defined by the World Health Organization.3 The authors concluded that “These results lay the groundwork for the ongoing clinical trial, PIONEER, with the AAV2.7m8-ChrimsonR-tdT vector for vision restoration in patients with retinitis pigmentosa.”
The paper is available at https://www.nature.com/articles/s42003-020-01594-w.
GenSight Biologics expect to release early findings in the first patients of the PIONEER trial later in the first half of 2021.
*About the paper:
Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates
Authors:
Gregory Gauvain1, Himanshu Akolkar1,2, Antoine Chaffiol1, Fabrice Arcizet1, Mina A. Khoei1, Mélissa Desrosiers1, Céline Jaillard1, Romain Caplette1, Olivier Marre1, Stéphane Bertin3, Claire-Maelle Fovet4, Joanna Demilly4, Valérie Forster1, Elena Brazhnikova1, Philippe Hantraye4, Pierre Pouget5, Anne Douar6, Didier Pruneau6, Joël Chavas6, José-Alain Sahel1,2,3, Deniz Dalkara1, Jens Duebel1, Ryad Benosman1,2, Serge Picaud1.
Affiliations:
1 Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.
2 Department of Ophthalmology, University Pittsburgh Medical Center, Pittsburgh, PA, USA.
3 CHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, F-75012 Paris, France.
4 Département des Sciences du Vivant (DSV), MIRcen, Institut d’imagerie Biomédicale (I2BM), Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), 92260 Fontenay-aux–Roses, France.
5 ICM, UMRS 1127 UPMC – U 1127 INSERM – UMR 7225 CNRS, Paris, France.
6 Gensight Biologics, 74 rue du faubourg Saint Antoine, F-75012 Paris, France.
References:
- Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, Flannery JG, Schaffer DV. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013 Jun 12;5(189):189ra76.
- Vicente-Tejedor J, Marchena M, Ramírez L, García-Ayuso D, Gómez-Vicente V, Sánchez-Ramos C, de la Villa P, Germain F. Removal of the blue component of light significantly decreases retinal damage after high intensity exposure. PLoS One. 2018 Mar 15;13(3):e0194218.
- World Health Organization, International Classification of Diseases 11 (2018):
https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1103667651