Startup Bags €50M Series A to Smash Gene Therapy Vector Limits

16/02/2022 - 5 minutes

After closing Spain’s largest biopharma Series A round, the company SpliceBio has set its foundations in the gene therapy field and joins the push to deliver bigger therapeutic genes into patients.

SpliceBio was founded in 2012 to tinker with a type of protein called inteins, which can stick peptides together to form new proteins. The firm, originally named ProteoDesign, was confronted with a dazzling array of potential applications for the technology and spent several years formulating its therapeutic mission: to push the limits of gene therapy technology.

We explored several areas, including antibody-drug conjugates, and realized that gene therapy was an area where our technology could have a huge impact, unmatched by any other technology, to address an extraordinary challenge that remained unsolved – the delivery of large genes in gene therapy,” said Miquel Vila-Perelló, CEO of SpliceBio.

This week, UCB Ventures and Ysios Capital led SpliceBio’s €50M Series A round — the largest in Spain’s biotech industry to date. It took place just months after Spain saw one of its biggest acquisition deals in biopharma: the takeover of Sanifit by Vifor Pharma for up to €375M.

With this new funding in hand, SpliceBio has firmly established its gene therapy focus and is creating a pipeline of treatments for genetic blindness conditions. SpliceBio’s lead program has its crosshairs on Stargardt disease, a condition caused by mutations in a retinal gene called ABCA4

According to Joël Jean-Mairet, Managing Partner of Ysios Capital, Stargardt disease is a big draw for investors and big pharma because the condition is well studied and is relatively easy for gene therapies to reach in the retina. 

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Despite being the most prevalent inherited retinal disorder caused by mutations in a single gene, patients currently do not have any therapeutic options to treat [Stargardt] disease,” added Jean-Mairet.

The biggest snag with Stargardt disease is that a healthy version of the ABCA4 gene is too big to deliver using the gold-standard gene therapy vector: adeno-associated viruses (AAV). AAV vectors can carry genes of up to roughly 5,000 base pairs in length; ABCA4 outstrips this at 6,800 base pairs. And other types of viral vectors with higher carrying capacities than AAV such as adenoviruses present other problems.

Adenoviruses are an excellent choice when your goal is to generate an immune response, such as in the case of Covid-19 vaccines, however their immunogenicity is problematic when the intention is to treat diseases of genetic origin,” said Miquel Vila-Perelló. “Lentiviruses also present significant safety risks and manufacturing challenges for in vivo gene therapy. We believe none of those are a viable option for in vivo gene therapy.

SpliceBio’s intein technology is designed to address the size obstacle by making some AAVs carry one half of the DNA sequence and other AAVs carry the other half. The AAVs are also equipped with DNA sequences for inteins. When an AAV carries the DNA into a cell, the cell turns the DNA sequence into half of the ABCA4 protein plus an intein. The inteins then splice together the two halves to make the full protein.

The technology resembles dual AAV vectors, an older form of gene therapy technology. The main difference from SpliceBio’s technology is that pieces of the gene are spliced together in the cell as DNA or RNA sequences before becoming a protein. However, Jean-Mairet told me that the approach is much less efficient than SpliceBio’s platform.

There are other methods in development to treat Stargardt disease with gene therapy. The most advanced contender is the US company Nanoscope Therapeutics, which is planning a phase I/IIa trial of its gene therapy for later this year. Rather than delivering the healthy ABCA4 gene, Nanoscope’s strategy is to make viral vectors deliver the gene for a light-sensitive, or ‘optogenetic’, protein. This way, the company can make retinal cells respond to light regardless of the mutation causing the condition.

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Another firm vying for a Stargardt disease gene therapy is Coave Therapeutics in France. Previously known as Horama, Coave aims to deliver the healthy ABCA4 gene using custom-designed AAV vectors, raising €33M in a Series B round in July 2021 to advance its pipeline. 

Many companies are also developing non-viral methods to deliver genes into patients, which face fewer size limits than viral vectors. For example, Nanoscope Therapeutics is developing a laser-based method to deliver genes directly into the eye, while Eyevensys in France uses electric currents. In late 2021, the Swiss firm Anjarium Biosciences raised a €51M Series A financing round to advance its own gene delivery system based on DNA vectors and nanoparticles.

Non-viral gene therapy vectors are relatively easy to manufacture and scale up to therapeutic quantities, which is still a challenge for viral vectors,” said Matthew Booth, Senior Vice President and Global Therapy Lead at the life sciences firm GenEra Consulting. “With that in mind, non-viral vectors may become the delivery vehicle of choice in diseases with high patient numbers.

Nonetheless, non-viral vectors are still at an early stage, with particular challenges in targeting specific organs. Vila-Perelló sees viral vectors continuing to play a crucial role in the evolution of gene therapies over the coming decade.

There is a reason why viral vectors and particularly AAVs are the vector of choice for in vivo gene therapy: they have evolved over millions of years in nature to carry out precise functions, and are undoubtedly the most advanced vectors to deliver life-changing therapies to patients,” Vila-Perelló concluded.

Cover image via Elena Resko

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