Methods and compositions for attenuating gene editing Anti-viral transfer vector immune responses

Abstract

Provided herein are methods and related compositions for administering viral transfer vectors and antigen-presenting cell targeted immunosuppressants.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119 of U.S. provisional application 62 / 047,034, filed Sep. 7, 2014; 62 / 051,255, filed Sep. 16, 2014; 62 / 101,841, filed Jan. 9, 2015; 62 / 047,044, filed Sep. 7, 2014, 62 / 051,258, filed Sep. 16, 2014; 62 / 101,861, filed Jan. 9, 2015; 62 / 047,054, filed Sep. 7, 2014; 62 / 051,263, filed Sep. 16, 2014; 62 / 101,872, filed Jan. 9, 2015; 62 / 047,051, filed Sep. 7, 2014, 62 / 051,267, filed Sep. 16, 2014; and 62 / 101,882, filed Jan. 9, 2015; the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to methods and compositions for administering viral transfer vectors and antigen-presenting cell targeted immunosuppressants.SUMMARY OF THE INVENTION[0003]Provided herein are methods and compositions for administering gene editing viral transfer vectors and antigen-presenting cell targeted immunosuppressants. The viral transfer vector comprises a gene editing tran...

AI Technical Summary

Benefits of technology

[0042]In one embodiment of any one of the methods provided herein, the antigen-presenting cell targeted immunosuppressant comprises a negatively-charged particle. In one embodiment of any one of the methods provided herein, the negatively-charged particle is a polystyrene, PLGA, or diamond particle. In one embodiment of any one of the methods provided herein, the zeta potential of the particle is negative. In one embodiment of any one of the methods provided herein, the zeta potential of the particle is less than −50 mV. In one embodiment of any one of the methods provided herein, the zeta potential of the particle is less than −100 mV.

[0043]In one embodiment of any one of the methods provided herein, the antigen-presenting cell targeted immunosuppressant comprises an apoptotic-body mimic and one or more viral transfer vector antigens. In one embodiment of any one of the methods provided herein, the apoptotic-body mimic is a particle that comprises the one or more viral transfer vector antigens. In one embodiment of any one of the methods provided herein, the one or more viral transfer vector antigens comprise one or more viral antigens. In one embodiment of any one of the methods provided herein, the particle may also comprise an apoptotic signaling molecule. In one embodiment of any one of the methods provided herein, the particle comprises a polyglycolic acid polymer (PGA), polylactic acid polymer (PLA), polysebacic acid polymer (PSA), poly(lactic-co-glycolic) acid copolymer (PLGA), poly(lactic-co-sebacic) acid copolymer (PLSA), poly(glycolic-co-sebacic) acid copolymer (PGSA), polylactide co-glycolide (PLG), or polyethylene glycol (PEG). In one embodiment of any one of the methods provided herein, the average diameter of the particle is between 0.1 and 5 μm, between 0.1 and 4 μm, between 0.1 and 3 μm, between 0.1 and 2 μm, between 0.1 and 1 μm or between 0.1 and 500 nm.

Problems solved by technology

Unfortunately, the promise of these therapeutics has not yet been realized in the art in a large part due to cellular and humoral immune responses against the viral transfer vector.

In addition, even if the level of pre-existing immunity is low, for example due to the low immunogenicity of the viral transfer vector, such low levels may still prevent successful transduction (e.g., Jeune, et al., Human Gene Therapy Methods, 24:59-67 (2013)).

Thus, even low levels of pre-existing immunity may hinder the use of a specific viral transfer vector and may require a clinician to choose a viral transfer vector based on a virus of a different serotype, that may not be as efficacious, or even opt for a different type of therapy if another viral transfer vector therapy is not available.

Additionally, viral vectors, such as adeno-associated vectors, can be highly immunogenic and elicit humoral and cell-mediated immunity that can compromise efficacy, particularly with respect to re-administration.

After viral transfer vector administration, neutralizing antibody titers can increase and remain high for several years and can reduce the effectiveness of readministration of the viral transfer vector, as repeated administration of a viral transfer vector generally results in enhanced undesired immune responses.

For many therapeutic applications, it is anticipated that multiple rounds of administration of viral transfer vectors will be needed for long-term benefits, and, without the methods and compositions provided herein, the ability to do so would be expected to be severely limited particularly if readministration is needed.

The problems associated with the use of viral transfer vectors for therapy is further compounded because viral transfer vector antigens can persist for some time, such as for at least several weeks, after a single administration (e.g., Nathawani et al., N Engl J Med 365; 25, 2011; Nathwani, et al., N Engl J Med 371; 21, 2014).

The persistence of antigen further hinders the ability to use viral transfer vectors successfully.

Prior to this invention, however, there was no way to do so and achieve long-term immune response attenuation without the need for long-term administration of an immunosuppressant.

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