Update 7/17/2015: Following my initial posting of this blog, I reached out to multiple companies – both public and private – to get clarification on their intentions to develop ‘next-generation’ novel AAV vectors. Updated information for these companies can be found in the table below and in each company’s respective section. Companies not included in the table were either not available for comment or are currently not exploring novel AAV vectors.
Update 7/31/2015: Updated Benitec's section with new details from their recently filed F-1.
One of the more interesting tidbits, in my opinion, mentioned on the AGTC webcast was in response to an analyst who was curious as to when this deal started to come together. According to management, the process began several months ago. As a reminder, AGTC announced their collaboration with 4D Molecular Therapeutics on April 20. Although it’s impossible to know if Biogen knew about AGTC’s access to next gen AAV vector technology when the collaboration started coming together, I suspect it probably gave AGTC more leverage during negotiations (assuming sub-licensing). Biogen is now the most recent big biopharma building out their gene therapy programs via collaborations with companies who have access to next generation AAV technology. This is only the latest development that supports my belief that novel vectors will play a critical role in the future of AAV gene therapy.
With the list of companies developing next-generation AAV vectors rapidly growing in 2015, I put together a list of these companies with some brief background.
At first glance, it becomes apparent that 4D Molecular Therapeutics has broad reach. This does not come as a surprise considering 4DMT has one of the most advanced directed evolution platforms (I previously stated this in my initial uniQure research ).
In addition to compiling some information on companies who have access to these next-generation vector technologies, I felt now would be an appropriate time to put some context behind why these technologies are so important for AAV gene therapies’ long term success.
Novel AAV Vectors for Outer Retinal Gene Therapy via Intravitreal Injection
For a brief background, the two common routes used for delivery of therapeutics to the retina are subretinal and intravitreal injection. Essentially, intravitreal injection delivers therapeutics in the middle of the eye (see below, left) while subretinal injection delivers therapeutics directly to the cells in the back of the retina (outer retinal layer). Intravitreal injection has been the go-to route for anti-VEGF therapies such as Regeneron’s (REGN) Eylea and Roche’s (RHHBY) Lucentis because – among other reasons – it is less invasive and safer than subretinal injection (explained below).
A recent David Schaffer (4DMT founder) paper discusses the development of novel AAV vectors for outer retinal gene therapy via intravitreal injection . Intravitreal injection has been an unsuccessful delivery route to date for gene therapy, which is why investigators have had to settle for subretinal injection thus far. Subretinal injection typically (injection into the green space, shown below, right) involves delivering the AAV vector via a small ‘bleb’ directly where the cells the AAV vectors need to transduce reside. In this case, the eventual transgene expression only originates from the relatively small percentage of cells that are close to the ‘bleb’. In addition, the subretinal injection causes temporary retinal damage (retinal detachment: the photoreceptor layer detaches from the RPE) and can possibly lead to serious structural and functional damage of these important cells in the outer retina.
Despite the numerous drawbacks of subretinal injection, it has been the go-to delivery route for gene therapy. This is because intravitreal injection has not been successful in the clinic due to the limitations of wild type AAV vectors currently used. These wild type vectors are simply unable to adequately migrate from the vitreous humour (see above) to the cells in the outer retinal layer . Ideally, AAV vectors should be delivered to the outer retina via intravitreal injection because – with a properly designed vector – it should lead to pan-retinal expression with minimal damage to the retina.
4DMT has previously generated novel AAV capsid variants that are capable of facilitating pan-retinal transgene expression in the retina of animals via intravitreal injection. Using directed evolution (shown below) in mice, 4DMT generated a novel AAV variant – termed 7m8 – that mediates highly efficient gene delivery to all retinal layers in mice and non-human primates .
The investigators also demonstrated that delivery of the novel 7m8 vector via intravitreal injection improved structure in the outer retina layer and rescued function in the X-linked Retinoschisis (XLRS) mouse model. Wild-type AAV2 and AAV8 vectors delivered via intravitreal injection did not lead to structural improvement and led to minimal transgene expression in the photoreceptors compared to the 7m8 variant (shown below) .
These results demonstrate the significant benefits of engineering novel AAV variants for gene delivery and serve as one example of why I believe gene therapy companies are investing in next-generation AAV vector technology.
Companies with Access to Next-Generation AAV Vector Technology
4D Molecular Therapeutics: Using their directed evolution platform developed at the University of California-Berkeley, 4DMT is building an in-house and partnered pipeline of next-generation vectors that target numerous tissue types :
Spark Therapeutics (ONCE): Spark recently presented preclinical data for their hemophilia B program (SPK-FIX). SPK-FIX uses a novel, rationally designed, AAV variant (AAV-Spark100) that maintains tissue tropism similar to AAV8. In addition, AAV-Spark100 has been less seroprevalent in humans than AAV2, AAV5, and AAV8. This is the first bioengineered AAV variant that Spark has publically disclosed, and it will enter the clinic around August.
UniQure (QURE): Entered an exclusive licensing agreement with 4DMT to develop novel AAV variants designed for liver and CNS applications in January 2014. UniQure is expected to make preliminary selection of these vectors in 2015, facilitating clinical development in 2016/2017 .
Avalanche (AAVL): Most likely acquired access to directed evolution IP via an exclusive licensing agreement with University of California in 2010 . Avalanche’s first next-generation vector pipeline candidate, AVA-201, uses a novel directed evolution AAV variant. AVA-201 is expected to enter IND-enabling studies in 2015. In May 2014, Avalanche entered into a collaboration with Regeneron to develop novel next-generation ophthalmic AAV gene therapies that modulate up to eight specified targets.
Update: I confirmed Avalanche acquired their directed evolution technology via a licensing agreement with University of California-Berkeley. In addition, Avalanche has the rights to the novel 7m8 vector discussed above.
Roche: Entered a collaboration with 4DMT in April 2015 to develop optimized next-generation AAV vectors for indications with high unmet medical need. It appears this collaboration focuses on monogenic ophthalmic indications.
AGTC: AGTC announced a collaboration and license agreement with 4DMT on April 20 to develop optimized AAV vectors to treat specific ophthalmic indications. On July 2, AGTC announced a collaboration with Biogen to develop gene therapies in ophthalmology. This collaboration includes:
Development of AGTC’s XLRS and X-Linked Retinitis Pigmentosa (XLRP) programs.
Biogen has options for early stage programs in AGTC’s pipeline: two ophthalmic diseases and one non-ophthalmic disease.
Biogen receives an exclusive license to use AGTC’s technology to develop AAV vectors for up to six genes, three of which are in AGTC’s discretion.
Update: I confirmed that the vectors developed via the collaboration with 4DMT can be utilized in the Biogen collaboration.
Voyager Therapeutics: Voyager has published a paper discussing the evaluation of novel chimeric AAV vectors developed via DNA shuffling (directed evolution), but the status of their development is unknown . In February, Voyager announced a collaboration with Genzyme/Sanofi (SNY) to develop novel AAV gene therapies for CNS disorders. This collaboration includes – but is not limited to – Voyager’s Parkinson’s disease (VY-AADC01), Friedreich’s ataxia (VY-FXN01), and Huntington’s disease (VY-HTT01) programs.
Asklepios BioPharmaceuticals (AskBio): AskBio previously investigated a novel, rationally designed, chimeric AAV2.5 capsid variant in a phase I clinical trial treating patients with Duchenne muscular dystrophy. Of note, this was the first clinical trial to employ a non-wild type capsid AAV vector in the clinic . One of AskBio’s founders, R. Jude Samulski, has published multiple papers describing the directed evolution and rational design of AAV vectors for gene therapy applications [8-10].
Baxalta (BXLT): Baxalta (formerly Baxter prior to spin-off) acquired Chatham Therapeutics in April 2014 in order to gain access to their hemophilia AAV gene therapy programs. Baxalta gained “broad access and intellectual property rights to [Chatham’s] gene therapy platform for the treatment of hemophilia B (BAX 335, currently in Phase I clinic trials) as well as preclinical hemophilia A (FVIII) program, and the potential future application to additional hemophilia treatments” . Chatham gained access to these technologies and intellectual property via their relationship with AskBio. I cannot confirm if this relationship allows Baxalta to leverage AskBio’s next-generation AAV technology to develop gene therapies for hemophilia.
Update: Baxalta would not comment if they had access to next-generation AAV technology from Asklepios.
Benitec (BNIKF, BNTC): In late 2014, Benitec entered into an exclusive licensing agreement with 4DMT to develop optimized AAV vectors with retinal specificity [12,13]. Per their recently filed F-1, it was revealed Benitec has exclusive access to novel 4DMT-developed AAV vectors for all ocular indications using ddRNAi. Benitec is planning on using novel AAV vectors in their two intravitreally injected AMD candidates – TT-211 and TT-231. TT-211 is being developed for the treatment of wet AMD and is a ddRNAi construct expressing a single shRNA targeting VEGF-A. Meanwhile, TT-231 is being developed for the treatment of both dry and wet AMD. TT-231 is a ddRNAi construct expressing three shRNAs targeting VEGFR-2, PDGF-ß, and human complement factor B. Benitec expects to have a vector candidate generated by 4DMT in the fourth quarter of 2015 and is anticipating an IND filing for TT-211 in the 2Q of 2017 .
GenSight Biologics (GNST) : GenSight Biologics is probably an AAV gene therapy company that is not on many people’s radar given they have only just filed their F-1. Gensight is developing GS030, a novel, rationally designed AAV2 gene therapy for the treatment of Retinitis Pigmentosa and dry AMD. Interestingly, GenSight plans to administer GS030 via intravitreal injection. GenSight is most likely opting for intravitreal injection because of the limited success seen in the clinic with subretinal injection, and also because the properties of the GS030 could make it amendable for intravitreal injection.
GS030 is utilizing a novel, rationally designed AAV2 vector termed AAV2.7m8. GenSight acquired the rights to utilize AAV2.7m8 for the treatment of numerous ophthalmic disorders via a licensing agreement with Avalanche. It would appear AAV2.7m8 is a wild-type AAV2 utilizing the “7m8 sequence” at position 588: LALGETTRP (as described in the 4DMT paper above). Based off the F-1 and publically available info, it is unclear if this true. I reached out to both Avalanche (no comment) and GenSight (not available) for clarification and unfortunately could not get any additional information.
EoS Neuroscience: Tested a rationally designed AAV8 vector in multiple mouse models of blindness.
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