SMAD7 gene delivery into muscle cells
Inventors
Rodgers, Buel Dantese • Gregorevic, Paul
Assignees
Baker IDI Heart and Diabetes Institute • Washington State University WSU
Publication Number
US-11268107-B2
Publication Date
2022-03-08
Expiration Date
2036-04-22
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Abstract
Described herein are vectors, such as adeno-associated virus (AAV) vectors, and recombinant AAV expressing Smad7. The disclosed AAV vectors and rAAV can be used for therapeutic applications in the treatment and amelioration of muscle wasting, cardiac and/or skeletal muscle wasting associated with cancer cachexia.
Core Innovation
The invention provides compositions and methods for muscle-specific expression of Smad7 using recombinant adeno-associated virus (rAAV) vectors, including but not limited to serotypes 6, 8, or 9. These vectors are engineered to deliver a Smad7 gene or cDNA directly into muscle cells, resulting in enhanced muscle mass and function, and prevention of muscle wasting in various pathological conditions. The construct may include tissue-specific promoters, enhancers, or silencers to further restrict expression to striated muscle or to cardiac muscle cells.
The problem addressed is the need for effective therapies for muscle wasting, such as that seen in cancer cachexia, without the off-target effects observed with current ActRIIB ligand trap interventions. Existing approaches that inhibit circulating ActRIIB ligands risk impacting other organ systems due to the pleiotropic nature of these ligands, resulting in adverse effects such as those seen in clinical studies of ligand traps (e.g., bleeding and vasodilation).
By targeting the intracellular ActRIIB pathway through Smad7 overexpression specifically in striated muscle using rAAV vectors, the invention aims to attenuate ActRIIB signaling, thereby reducing muscle catabolism and preserving muscle mass and strength. This strategy was demonstrated to be effective in preventing muscle wasting across multiple models, including cancer cachexia, diabetes, obesity, cardiovascular diseases, aging, and genetic models of cachexia, without causing detectable expression or effects in non-muscle tissues.
Claims Coverage
There are two independent claims focusing on compositions for muscle-targeted Smad7 gene delivery using recombinant AAV constructs.
Composition of Smad7 gene or cDNA in rAAV for muscle-targeted expression
A composition comprising a Smad7 gene or cDNA in a recombinant adeno-assisted virus (rAAV) construct, wherein: - The rAAV construct is serotype 6 (rAAV6), serotype 8 (rAAV8), or serotype 9 (rAAV9). - The rAAV construct provides expression of the Smad7 gene or cDNA in muscle cells. Additional inventive aspects covered by dependent claims include: - rAAV6 as the specific serotype. - Inclusion of tissue-specific promoters, enhancers, or silencers to direct or limit expression to muscle cells or specific muscle types (e.g., cardiac, skeletal, or heart). - The Smad7 gene or cDNA may be from various species (human, mouse, equine, bovine, ovine, canine, or porcine).
Composition of human Smad7 gene or cDNA in rAAV for muscle expression
A composition comprising a Smad7 gene or cDNA of human origin in a recombinant adeno-assisted virus (rAAV) construct, where: - The rAAV construct is serotype 6 (rAAV6), serotype 8 (rAAV8), or serotype 9 (rAAV9). - The rAAV construct provides expression of the human Smad7 gene or cDNA in muscle cells.
The independent claims cover compositions for Smad7 gene or cDNA delivery via rAAV constructs of specific serotypes targeting muscle cells, optionally including human sequences and elements to direct or restrict expression to muscle tissue.
Stated Advantages
The approach reduces or eliminates off-target effects compared to circulating ligand traps for ActRIIB, as Smad7 expression is limited to muscle tissue.
Systemic administration of rAAV:Smad7 specifically increases muscle mass and function and prevents muscle wasting in various models, including cancer cachexia, without affecting non-muscle tissues.
Attenuation of ActRIIB signaling using muscle-targeted Smad7 provides a novel and effective strategy for both prevention and treatment of muscle wasting disorders.
The method enables both therapeutic (treatment of muscle wasting) and cosmetic (enhancement of muscle mass/strength in healthy individuals) applications.
Documented Applications
Therapeutic treatment and amelioration of muscle wasting, including cardiac and skeletal muscle wasting associated with cancer cachexia.
Treatment and prevention of muscle wasting resulting from chronic disorders such as aging (sarcopenia), muscular dystrophy, myopathies, kidney disease, chronic obstructive pulmonary disorder, chronic infection, AIDS, disuse atrophy, neuromuscular injury, neuropathies, obesity, cardiovascular disease, or combinations thereof.
Prevention of muscle wasting caused by microgravity stress.
Enhancement of muscle mass and/or strength in healthy subjects for cosmetic or elective purposes.
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