Portfolio | Gene Therapy

Striving to solve gene therapy’s most pressing challenges
Image

Selecta & Gene Therapy

Selecta’s solutions for gene therapy

Selecta’s therapies have the potential to enhance the efficacy and safety of gene therapy while also mitigating unwanted immune responses, improving accessibility by addressing pre-existing anti-AAV antibodies and inducing AAV-specific tolerance to enable redosing of gene therapy.

ImmTOR® has shown significant first dose benefits when co-administered with a gene therapy including: improved transduction, more durable transgene expression, inhibition of liver inflammation and stabilization of hepatic stress.  Beyond this, Selecta has shown in a clinical trial the ability to inhibit the formation of neutralizing antibodies to AAV8 capsids out to 30 days.  This data opens the potential to transform the dosing paradigm of gene therapy from “one and done” to “low and slow”.  By giving multiple lower doses of a gene therapy, we could potentially titrate up to the intended therapeutic level while avoiding the unfortunate adverse events that have been seen at high doses of gene therapy.

Xork, Selecta’s proprietary IgG protease, has shown the ability to cleave human IgG and potentially open a treatment window in which patients can be dosed with an AAV gene therapy.  Currently, 30-70% of patients are excluded from gene therapy trials due to pre-existing antibodies.

Selecta’s novel approach to treating systemic diseases resulting from genetic disorders has the potential to overcome major hurdles in gene therapy.

Unlocking the Potential of AAV Gene Therapy

  • The Challenges

    AAV vectors are non-replicating, so transgene expression is expected to wane over time, especially in children, most likely necessitating re-dosing. As many gene therapies in development are being investigated for the treatment of rare, often lethal, pediatric disorders, the inability to re-dose these therapies are of particular concern.

    The formation of neutralizing antibodies after AAV vector administration prevents redosing due to the potentially dangerous immune response that would follow a second or third gene therapy administration.  Adverse patient events related to high vector doses are inextricably linked to immunogenicity.

    Pre-existing immunity to AAV vectors excludes significant numbers of patients who would potentially benefit from treatment by AAV gene therapy.

  • The Solution

    ImmTOR® has the potential to induce AAV-specific immune tolerance, reducing the severity of the body’s immune response to AAV gene therapy and enabling repeat administrations.

    Redosing is important when determining the optimal dose

    Image

    Establishing the optimal dose for a patient can sometimes require repeat administrations.

    Redosing can help rescue therapeutic benefits over time

    Image

    Genetic metabolic diseases often manifest early in childhood. However, AAV vectors are nonreplicating, so transgene expression is expected to wane over time as pediatric patients grow.

    Xork has the potential to selectively metabolize pre-existing anti-AAV antibodies that prevent patients from receiving initial doses of AAV gene therapy.

  • The Opportunity

    Aiming to simultaneously address two key challenges in AAV gene therapy.

    ImmTOR®, by inhibiting the formation of neutralizing antibodies, could make redosing of gene therapy possible.  Functional benefit could be maintained or restored with additional doses. Safer and more efficacious dosing regimens could be implemented.

    Up to 30%-70% of patients are ineligible for gene therapy due to pre-existing anti-AAV antibodies to naturally occurring AAVs in the environment. Xork could potentially make these patients with pre-existing immunity to AAV vectors eligible for treatment.

    Selecta has partnered its technologies with leading gene therapy companies including Takeda, AskBio and Sarepta to develop gene therapies that have the potential to be safer, more efficacious, and more durable.

Supporting data

ImmTOR™ induces specific tolerance

Clinical Validation

A single dose of ImmTOR® has been observed to inhibit the formation of neutralizing antibodies to AAV vectors in humans up to 30 days. Combined with extensive preclinical work in non-human primates that suggest additional monthly doses to prevent neutralizing antibody formation, ImmTOR® has the potential to inhibit the formation of neutralizing antibodies associated with gene therapy.

Preclinical Validation

ImmTOR®

Extensive preclinical data in non-human primates suggest that two “low” doses of AAV gene therapy with ImmTOR® may provide comparable expression as a single “high” dose of AAV gene therapy. Additionally, monthly doses of ImmTOR® have been associated with durable prevention of neutralizing anti-AAV antibodies in preclinical studies.

Image

Xork

Xork is an IgG protease derived from a non-human pathogen that cleaves human IgG specifically and efficiently but shows low cross reactivity to human sera. Xork can potentially open a treatment window for those with pre-existing immunity to AAV vectors.

Pre-existing anti-IgG protease antibodies in human serum

Pipeline

Selecta + gene therapy

Selecta’s first ImmTOR® + gene therapy program for methylmalonic acidemia (SEL-302) is expected to enter clinical trials in the second half of 2022.

Additional programs in pre-clinical development are in Pompe disease (in partnership with AskBio), Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (both in partnership with Sarepta), and two lysosomal storage disorders (in partnership with Takeda Pharmaceuticals). Xork (SEL-018) is also in preclinical development to assess efficacy in removing anti-AAV neutralizing antibodies.

Wholly-Owned Pipeline

Indication

Antigen

Stage of Development

Preclinical
Phase 1
Phase 2
Phase 3

Upcoming Milestone

Commercial Rights

Unlocking the potential of Gene Therapy

Gene Therapies

Methylmalonic acidemia (MMA)

0

AAV (serotype undisclosed)

0

52

SEL-302

Phase 1 start 2H 2022

0

0

Gene Therapy

0

IgG protease IdeZork (Xork)

0

28

SEL-018

0

0

Ornithine Transcarbamylase
deficiency
(OTCD)

0

AAV-hOTC

0

28

SEL-313

Paused

0

0

Partnered

Indication

Antigen

Stage of Development

Preclinical
Phase 1
Phase 2
Phase 3

Upcoming Milestone

Commercial Rights

Unlocking the potential of Gene Therapy

Gene Therapies

Pompe disease

0

Undisclosed

0

20

0

0

Duchenne muscular dystrophy (DMD)

0

Undisclosed

0

20

0

0

Limb-girdle muscular dystrophy (LGMD)

0

Undisclosed

0

20

0

0

Two indications for lysosomal storage disorder

0

Undisclosed

0

20

0

0

SEL-302 in Methylmalonic Acidemia (MMA)

Selecta’s first gene therapy program SEL-302 combines ImmTOR® with MMA-101, an AAV gene therapy vector for treatment of methylmalonic acidemia (MMA).

MMA is a rare metabolic disease that affects the ability of the body to metabolize certain amino acids and fats and may lead to metabolic acidosis, hyperammonemia and long-term complications including feeding problems, developmental delays, intellectual disability and chronic kidney disease.

SEL-018 in improving patient eligibility

Selecta’s wholly owned IgG protease Xork has the potential to expand patient eligibility for life-altering gene therapy treatments.

Currently, pre-existing IgG antibodies against AAV gene therapy vectors are a major exclusion criterion for AAV gene therapy eligibility, affecting upwards of 30-70% of the population. Xork, an IgG protease derived from a non-human pathogen, specifically and efficiently cleaves human IgG and can potentially open a therapeutic window for AAV gene therapies by depleting anti-AAV antibodies.

It is differentiated from IgG proteases derived from Streptococcus pyogenes, a common human pathogen, and shows low cross-reactivity to antibodies in normal human serum. We believe that the combination of ImmTOR® and Xork could simultaneously address two major challenges facing the AAV gene therapy modality: AAV immunogenicity and AAV toxicity.

Partner with us

Learn more about partnership opportunities

Selecta has partnered with leading gene therapy companies, including Takeda, AskBio and Sarepta Therapeutics to evaluate the potential of ImmTOR® in combination with AAV gene therapy. Selecta is also looking for partnerships to unlock the potential of its proprietary IgG protease, Xork, for the mitigation of pre-existing anti-AAV antibodies.

Publications

Validated and peer-reviewed research

Our research is validated by a long track record of peer-reviewed publications in high-impact journals in collaboration with our industry and scientific partners.