LONDON – After announcing its $17.4 million series A funding in the midst of pandemic in April, Genespire Srl has now gone public on the preclinical research upon which its programs will be based, presenting the data at last week’s American Society of Gene and Cell Therapy (ASGCT) annual meeting.
The lead program will focus on autologous ex-vivo gene editing of T cells and hematopoietic stem cells to correct inherited mutations of the CD40 ligand gene that impair antibody responses and innate immunity. The second program aims to use lentiviral vectors that integrate into liver cells to impart long-lasting effects in metabolic disorders.
Preclinical proof of concept for both was presented at ASGCT on May 14.
The two programs “are each based on technologies that are strongly differentiated,” said Julia Berretta, CEO of Genespire. “One of the leading factors in their selection is unmet medical need. We can tackle disease and really make a difference,” she told BioWorld.
April in Italy, when the country was in the thrall of COVID-19, hardly seems an auspicious time to be launching a company. But, Berretta said, it is important to look at Genespire’s roots, as a spin-out of one of the world’s leading gene therapy centers, the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan, and at its co-founder, gene therapy pioneer Luigi Naldini.
“The company is very young, but is based on technologies that have matured in the last 20 years. [SR-Tiget] is world renowned. I’m happy to have the company based on such great science,” Berretta said.
With non-COVID-19 clinical trials suspended and academic labs closed or repurposed for pandemic research, the work of many biotechs is being held back.
However, Genespire’s stage of development makes it relatively immune to the effects of the crisis. “I don’t expect much influence on performance,” said Berretta. “We’re not in the clinic yet, so we’re probably not impacted as much as others,” she said. “People are working remotely and labs are restarting, with Italy coming out of lockdown.”
That means the serious work can now begin following the April closing of the $17.4 million series A investment from Sofinnova Partners’ Italian gene therapy fund. Berretta, who previously was vice president of business development at allogeneic CAR T specialist Cellectis SA, also is CEO of another company backed by the Sofinnova fund, Epsilen Bio Srl, which is developing epigenetic silencing techniques to switch off expression of disease-related genes.
Preclinical proof of concept
Berretta estimates it will take two to three years to get Genespire’s lead gene therapy program, treating the inherited immune system disorder X-linked hyper IgM syndrome (HIGM1), into the clinic.
Defective CD40 signaling means HIGM1 patients produce normal or elevated levels of IgM, but very low levels of other immunoglobulins. That leads to an enhanced susceptibility to infections and an increased risk of cancer.
Current standard of care involves immunoglobulin replacement and antibiotic and antifungal therapy. Bone marrow transplants are possible if matched donors can be found.
Gene editing of autologous T cells could both resolve infections and bridge toward a bone marrow transplant.
The Genespire data presented at ASCGT showed that infusing corrected T cells into HIGM1 mice resulted in stable T-cell engraftment and a partial correction of antigen-specific IgG responses. The effect was sufficient to control pneumocystis, a common opportunistic pulmonary infection.
Following on from that, CRISPR/cas9 gene editing was used to correct human T cells and hematopoietic stem cells. Both promoted a protective immune response in a mouse model of HIGM1.
“We have shown the [gene editing approach] works in human cells and animal models, so we have got preclinical proof of concept. Our main objective is to bring this to the clinic in the best possible way,” Berretta said.
The second program will build on a liver-directed lentiviral vector delivery system, developed over the past decade by Genespire co-founder Alessio Cantore, to address the fact that adeno-associated vectors currently used to target genes to the liver cells are not suitable for people with neutralizing antibodies, or for children whose livers are still growing.
The lentiviral vector construct uses a vesicular stomatitis virus containing a hepatocyte-specific promoter, to achieve stable gene expression. In preclinical research, Cantore has shown it is possible to achieve transgene expression over 3.5 years in dogs administered the gene therapy construct at 2 to 4 months of age.
To prevent immune system rejection, the vectors are engineered with a high surface content of the leukocyte surface antigen CD47, a natural inhibitor of phagocytosis.
The program is riding on the shirt tails of a deal SR-Tiget has with Sanofi SA subsidiary Bioverativ Inc., to develop the lentiviral vectors for treating hemophilia.
Genespire is not saying which metabolic disorders it intends to target with the liver-directed lentiviral vectors. “We are looking at indications of interest but not disclosing which at the moment. This is [at] an earlier stage, but it is validated in nonhuman primates, so it is partially derisked and already advanced in hemophilia,” said Berretta.