Gene Therapy

Selecta Biosciences, Inc. is applying its SVP™ technology to antigen-specific immune tolerance to gene therapy.

In collaboration with Genethon, a not-for profit company focusing on gene therapies, we conducted a preclinical study in mice in which we observed the ability of SVP-Rapamycin to mitigate the formation of ADAs to AAV-based gene therapy vectors, thereby enabling repeat dosing.

Selecta has obtained an exclusive license to Anc80, an in silico designed gene therapy vector, from Massachusetts Eye and Ear. Anc80 has demonstrated the potential to provide superior gene expression levels in the liver compared to naturally-occurring adeno-associated viral vectors (AAVs) that are currently in clinical development. Anc80, a next-generation engineered gene therapy vector, is synthetic in nature and has been shown to have reduced cross-reactivity with commonly used AAV vectors.

Gene therapy is a promising area that often uses naturally-occurring viruses (like AAV) or engineered compounds (like Anc80) as a delivery mechanism to place corrective genetic material into cells to treat genetic diseases. In clinical trials, AAV vectors have been observed to induce undesired immunogenicity, which potentially limits the durability of the efficacy of the first dose of gene therapy and significantly reduces the efficacy of any subsequent dose of the gene therapy. Based on our preclinical data, we intend to develop SVP-Rapamycin (SEL-110) to enable repeat dosing of viral vector based gene therapies via systemic routes of administration.

Undesired immunogenicity can manifest itself in three ways. First, pre-existing neutralizing anti-drug antibodies (ADAs) induced following a natural AAV infection can block gene transfer. Today up to 50 percent of patients are ineligible for gene therapy due to the presence of pre-existing ADAs. Second, ADAs form in response to a first administration of a gene therapy vector and prevent effective subsequent doses of gene therapy. The ability to re-administer is important for therapeutic targets that undergo renewal which is the case in many pediatric indications.  The ability to re-administer gene therapies is also important for diseases where the goal is to transfect a high number of cells. Lastly, cellular immune responses against the transduced cells can reduce efficacy and pose safety concerns. Selecta intends to combine Anc80 with SVP-Rapamycin with the objective to address all three of these immunogenicity issues related to gene therapies.

Methylmalonic Acidemia (MMA)
Our first gene therapy program with Anc80 is targeted to treat Methylmalonic Acidemia (MMA), which is an inborn error of metabolism that affects approximately one in 50,000 newborns in the United States. Patients cannot process certain proteins and fats leading to accumulation of toxic metabolites. Symptoms start to develop in early childhood and despite strict diet, patients suffer from a wide range of disease-related complications. Selecta intends to combine the gene therapy vector Anc80 with transgenes discovered in the Venditti laboratory at the National Human Genome Research Institute (NHGRI) and Selecta’s SVP-Rapamycin (SEL-110) to create a new product candidate designed to incorporate several features that are important for a gene therapy approach in MMA. The objective of the development program is to address the ability to treat patients with pre-existing antibodies; the ability to administer several doses to achieve sufficient levels of methylmalonyl-CoA mutase (MUT), the enzyme that MMA patients are lacking; and the prevention of cellular immune responses that often reduce the expression levels of gene therapies. To advance the MMA program, Selecta has entered into a Collaborative Research and Development Agreement (CRADA) with MEE and NHGRI.

Ornithine Transcarbamylase Deficiency (OTC)
Our proprietary program for Ornithine Transcarbamylase Deficiency (OTC) combines an adeno associated virus (AAV)-based gene therapy with Selecta’s SVP-Rapamycin (SEL-110). The combination of both products is designed to enable repeated doses of the gene therapy treatment, which may be required when treating infants and young children with this disease to maintain required expression levels of the missing OTC enzyme. The treatment approach would also be designed to prevent liver damage that can be associated with cellular immune reactions to gene therapy vectors such as AAV. OTC, an inborn error of metabolism,  has an incidence of approximately one in 70,000 live births in the United States and Europe. In patients with OTC, consumption of protein results in the accumulation of undesirable levels of ammonia in the blood, which can cause irreversible brain damage. Patients with the most severe form of the disease require liver transplantation in early childhood and suffer intellectual disability, developmental delays and reduced life expectancy. To advance the OTC program, Selecta has entered into a CRADA with the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.

Mitigation of ADA - Gene Therapy


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