Production and delivery of a stable collagen
Inventors
Marinkovich, M. Peter • Lane, Alfred T. • Rajadas, Jayakumar
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-9403895-B2
Publication Date
2016-08-02
Expiration Date
2032-04-26
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Abstract
Improved methods are provided for the recombinant synthesis of collagen, particularly collagen VII, in host cell, and for therapeutic delivery of the same. The recombinant collagen is produced in a host cell that has increased levels of prolyl-4-hydroxylase, relative to basal cell levels. The collagen produced by the methods of the invention has increased numbers of modified proline residues, relative to a recombinant collagen produced in a host cell having basal levels of prolyl-4-hydroxylase. The increased proline modification provides for a collagen having increased stability, including increased in vivo stability.
Core Innovation
The invention provides improved methods for the recombinant synthesis of collagen, particularly collagen VII, in a host cell with increased levels of prolyl-4-hydroxylase relative to basal cell levels. This leads to recombinant collagen having increased numbers of modified proline residues compared to collagen produced in host cells with basal levels of prolyl-4-hydroxylase. The increase in proline modification enhances collagen stability, including increased in vivo stability exemplified by increased half-life after injection.
Additionally, the invention presents delivery devices and methods for therapeutic proteins comprising microneedle arrays made of biocompatible or biodegradable polymers loaded with collagen VII. These microneedles penetrate the skin to the epidermal/dermal junction, enabling effective delivery of stable collagen for treatment of acquired or genetic diseases such as epidermolysis bullosa. Pharmaceutical formulations comprising stable recombinant collagen VII and pharmaceutically acceptable excipients are also described, including forms administered via dissolvable microneedle arrays or for topical use.
Claims Coverage
The patent includes six inventive features primarily covered by three independent claims related to methods and compositions involving recombinant collagen VII production and delivery via biodegradable microneedles.
Method of delivering collagen VII using biodegradable microneedles
A method comprising fabricating an array of biodegradable microneedles incorporating collagen VII and contacting skin with the array using sufficient pressure to penetrate to the depth of anchoring fibrils in the dermal layer.
Recombinant collagen VII synthesis with increased prolyl-4-hydroxylase expression
Producing collagen VII by synthesizing recombinant collagen VII in a host cell genetically modified to overexpress prolyl-4-hydroxylase, resulting in collagen with increased stability incorporated into the microneedles.
Biodegradable microneedle arrays comprising recombinantly produced collagen VII
Arrays of biodegradable microneedles containing collagen VII produced in host cells overexpressing prolyl-4-hydroxylase, wherein the collagen shows increased stability compared to that from cells lacking such modification.
The claims cover methods of delivering stable recombinant collagen VII using biodegradable microneedle arrays, the production of collagen VII with enhanced stability via prolyl-4-hydroxylase overexpression, and the compositions of microneedle arrays incorporating such collagen for therapeutic delivery.
Stated Advantages
Increased stability of recombinant collagen VII due to enhanced proline hydroxylation, leading to greater in vivo half-life.
Provision of a targeted and efficient delivery method of collagen VII to the epidermal/dermal junction using biodegradable microneedle arrays.
Ability to deliver therapeutic proteins painlessly and accurately over large surface areas, improving patient comfort and treatment effectiveness.
Documented Applications
Treatment of acquired or genetic epidermolysis bullosa, including recessive and dominant dystrophic forms, through delivery of stable recombinant collagen VII.
Therapeutic delivery of collagen VII to the dermal layer of skin for wound healing and incorporation into anchoring fibrils.
Use of microneedle arrays for delivering collagen VII and potentially other therapeutic proteins to patients with skin diseases lacking functional collagen VII or other related proteins.
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