Skeletal Muscle Gene Delivery: History
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Contributor:
Zhanpeng Cui
,
Yang Jiao
,
Linyu Pu
,
James Zhenggui Tang
,
Gang Wang

Since Jon A. Wolff found skeletal muscle cells being able to express foreign genes and Russell J. Mumper increased the gene transfection efficiency into the myocytes by adding polymers, skeletal muscles have become a potential gene delivery and expression target. Different methods have been developing to deliver transgene into skeletal muscles. Among them, viral vectors may achieve potent gene delivery efficiency. Therefore, non-viral biomaterial-mediated methods with reliable biocompatibility are promising tools for intramuscular gene delivery in situ. A series of advanced non-viral gene delivery materials and related methods have been reported, such as polymers, liposomes, cell penetrating peptides, as well as physical delivery methods.

  • non-viral materials
  • gene delivery
  • skeletal muscle

1. Introduction

Due to the wide distribution and enormous number of skeletal muscles in the human body, it has high application value to deliver functional genes into skeletal muscle cells for target protein expression. Skeletal muscles can act as protein factories, wherein exogenous functional genes can serve as “blueprints” to produce target proteins for specific purposes, such as antibodies for cancer immunotherapy[1] and insulin analogues for diabetes treatment[2]. Delivery of exogenous genes into cells needs vectors, which are mainly divided into viral vectors and non-viral vectors. Although viral vectors had high gene delivery efficiency, their potential biosafety risks limited the clinical applications[3]. In 1990, Jon A. Wolff[4] first reported that skeletal muscles could take up plasmid DNA (pDNA) and express the reporter protein. In the experiments, naked pDNA carrying LacZ gene was directly injected into a quadriceps muscle of mice and seven days later, the whole muscle was removed and stained by X-Gal. The stained cross-section of the muscle tissue showed that the target gene could be expressed in muscle cells to a certain extent. However, it is difficult to acquire high gene delivery efficiency and expression level via direct injection of naked pDNA into skeletal muscles.
Transfection of pDNA into cultured cells is a process in which cells actively or passively acquire foreign DNA in a simple in vitro environment. The main barriers of gene transfection include cell plasma membrane, escape of genes from endosomes and lysosomes, detachment of genes from gene carriers, nuclease, and cell nuclear membrane, etc. [5][6]. In comparison, delivery of pDNA into skeletal muscle cells is carried out in a more complex in vivo environment, so it is confronted with extracellular and intracellular obstacles. Before penetrating the cell plasma membrane, it needs to overcome the extracellular obstacles first. Owing to the large size and negative charge of pDNA molecules, naked pDNAs can be easily trapped or damaged by extracellular obstacles, such as extracellular matrix (ECM), biomacromolecules with positive charge as well as nuclease in the ECM [5](Scheme 1). To solve this problem, Russell et al. combined polyvinyl pyrrolidone (PVP, Table 1) and polyvinyl alcohol (PVA) with pDNA in mixed solution and injected the solution into the tibialis anterior (TA) muscles, generating improved expression level of exogenous genes compared to naked pDNA injection [7]. The study showed that gene delivery efficiency into skeletal muscles could be improved by some non-viral biomaterials.
Pharmaceutics 14 02428 sch001
Scheme 1. Differences between gene delivery in vivo and transfection in vitro.
Table 1. Polymers for gene delivery to skeletal muscles.
Polymers Year Reporter Genes Functional Genes Function
Polyvinyl pyrrolidone (PVP) 1996 [7] CAT, β-CAT /
  • Detecting gene expression
Pluronic P85® 2005 [8] Luc /
  • Detecting gene expression
2009 [9] GFP, Luc /
  • Detecting gene expression
2016 [10] Luc, GFP pDRIVE5Lucia-mDesmin & pDRIVE5GFP-mDesmin
  • Treating hind limb ischemia in mice
Multi-block copolymers from Pluronic P85 and di-(ethylene glycol) divinyl ether® 2009 [11] Luc /
  • Detecting gene expression
Pluronic SP1017® 2005 [8] Luc /
  • Detecting gene expression
Pluronic 25R2® 2011 [12] Luc /
  • Detecting gene expression
Pluronic L64® 2002 [13] Luc, β-Gal /
  • Detecting gene expression
2014 [14] / HIF-1α
  • Treating severe hind limb ischemia in mice
2019 [15] lacZ, Luc, E2-Crimson GHRH
  • Detecting gene expression
  • Accelerating mouse growth
2021 [1] E2-Crimson, EGFP mlFVII Icon
  • Detecting gene expression
  • Tumor Immunotherapy
PEG13-PLGA10-PEG13 2007 [16] Luc VEGF
  • Detecting gene expression
PEO–PTHF–PEO 2008 [17] Luc, lacZ /
  • Detecting gene expression
LPL 2014 [18] lacZ, Luc, E2-Crimson mGH
  • Detecting gene expression
  • Accelerating mouse growth
rL2PL2, rL3PL3 2016 [19] lacZ, Luc, E2-Crimson GHRH
  • Detecting gene expression
  • Accelerating mouse growth
TBCPs 2020 [20] Luc /
  • Detecting gene expression
Lutrol 2005 [21] Luc /
  • Detecting gene expression
Poloxamine 304
poly(D, L-lactide-co-glycolide) 2006 [22] Luc /
  • Detecting gene expression
PLGA/E100 2009 [23] / IL-10
  • Treating type 2 diabetes
HCPEI 2008 [24] / VEGF
  • Treating mouse ischemic limb
TAEI-PEI 2012 [25] GFP /
  • Detecting gene expression
PLGA 2008 [26] / VEGF
  • Treating mouse ischemic limb
PEG-PAMAM 2009 [3] EGFP /
  • Detecting gene expression
PAMAM-G5/SMTP/DBP/NLS mixture 2021 [27] EGFP micro-dystrophin (µDys)
  • Detecting gene expression
  • Treating Duchenne Muscular Dystrophy
In contrast to the prosperity of non-viral vectors regarding in vitro gene transfection of cells and in vivo targeted gene delivery through the bloodstream, there were limited studies on non-viral vectors and related methods for skeletal muscle gene delivery [28].

2. Advantages and Challenges of the Skeletal Muscle Gene Delivery

For the traditional gene therapy, the therapeutic genes were usually sent to the lesion cells, such as in cancer treatment[29][30][31]. However, for the skeletal muscle-based gene therapy, the delivery targets were skeletal muscle cells. Previous studies have screened the muscle-specific promoter [32], proving that skeletal muscle has microbubbles, which can bring the protein secreted out of the cells, affect the adjacent cells, and regulate the behaviour of them [33]. In addition, proteins secreted by muscle cells can also enter the circulatory system and affect physiological parameters, such as hormone secretion, and nervous and immune system activity [34]. Based on the above points, some scientists have successfully introduced the vector carrying insulin gene into skeletal muscle with genetic engineering technology and used it to treat Type 1 diabetes [35]. After that, another study showed that the co-expression of insulin and glucokinase could be applied to correct hyperglycaemia and prevent hypoglycaemia [36]. It can be concluded that in these systems, skeletal muscle cells played the role as protein factories, rather than a lesion site.

2.1. Advantages of the Skeletal Muscle as the Target for Gene Delivery

Skeletal muscles have many inherent anatomical, cellular, and physiological characteristics. It is a good target tissue for gene expression, especially for the production of proteins such as systemic therapeutic agents. The significant advantages of skeletal muscle as a target tissue for gene delivery can be mainly attributed to four points:
(1) The weight of skeletal muscles accounts for 30% of a normal adult’s weight, which means there is enough target tissue for gene delivery; (2) Skeletal muscles have rich vascular systems. Abundant capillary networks wrap each muscle fiber at regular intervals, thus providing an effective transportation system for secreted proteins to enter the circulation; (3) Skeletal muscle fibers contain terminally differentiated cells, and the nuclei in the fibers are postmitotic. A single muscle fiber can survive in the living body for a long time. Even if muscle fibers are damaged and only a short segment of some fibers is unimpaired, the nucleus of surviving muscle can still work [37]. It provides a stable environment for the continuous production of proteins; (4) In muscle fibers, foreign genes can be spread from a limited injection site to the nuclei of a large number of adjacent muscle cells in the fiber. This ability to diffuse foreign genes in muscle fibers is probably one of the reasons why foreign genes can be highly expressed in muscles [28].
Therefore, skeletal muscles are expected to become a potential target tissue for gene therapy. Gene delivery to skeletal muscle is simple as it only requires intramuscular injection, differing from long-term daily insulin injection or radiotherapy and chemotherapy.

2.2. Obstacles to Skeletal Muscles Gene Delivery

Systemic administration of genes transports foreign vectors through the circulatory system, which may face obstacles of off-target effects on other organs and stability changes in serum. As a local injection method, gene delivery to skeletal muscle cells allows direct injection of prepared plasmid DNA. Therefore, the obstacles mainly exist in the ECM, cytoplasmic membrane, endosome escape, and nuclear entry.

2.2.1. Obstructions in the Extracellular Matrix

Unlike other ECMs, the ECM of the skeletal muscle is a three-dimensional scaffold composed of various collagens, glycoproteins, proteoglycans, and elastin[38] , and many of these proteins are negatively charged [39].
Generally, the delivery efficiency of most gene carriers, such as liposomes and polymers, is much lower than that of viral vectors. Unlike other organs, muscle fibers are surrounded by a mechanically strong ECM, which is the glycosaminoglycan-rich basement membrane in the skeletal muscle [40][41][42] and the ECM is strongly negatively charged. As a result, cationic liposomes and polymers are very easily bound to the negatively charged biomacromolecules in the ECM, which hinders the entry of cationic DNA/carriers complexes into cells [43].
Naked plasmids have shown to be useful for gene transfer into skeletal muscles[4], but low transfer efficiency brought great challenges to clinical promotion. Studies have shown that adding nuclease inhibitors could improve the transfer efficiency of pDNA into muscles [44], which proved that nuclease was also one of the main factors in ECM that inhibited pDNA transfer efficiency.

2.2.2. Cytoplasmic Membrane

The existence of the cell membrane provides a relatively stable environment for the cell. The main structure of the cytoplasmic membrane is a phospholipid bilayer containing phospholipid molecules, cholesterol, and proteins embedded in the membrane or on the membrane surface. Highly hydrophilic and bulky pDNA molecules are easily blocked due to the existence of the amphiphilic bilayers in the cytoplasmic membrane. Therefore, how the gene and the carrier cooperate to cross the cytoplasmic membrane and enter the cell is also a key issue in gene delivery. So far, the methods used to improve the delivery efficiency of pDNA mainly included adding components that could promote the internalization of DNA into target cells, such as transferrin[45] , organic solvents, nonionic polymers or surfactants, etc. [5]. According to the properties of these substances, these additives were speculated to temporarily change the permeability of the cytoplasmic membrane by disturbing the cytoplasmic membrane, and therefore allowing pDNA to penetrate the membrane more easily [46]. In addition to adding the above substances, some physical methods could temporarily create non-lethal pores in the cell membrane to facilitate the passage of pDNA, such as gene gun[47] , electroporation[48] , ultrasonic microbubble[49] , and hydrodynamic[50]  methods.

2.2.3. Endosomal Escaping

For osmotic and invasive delivery methods, genes generally enter the cytoplasm directly through the cytoplasmic membrane and do not involve endosomal escape. The delivery method of genes into cells by endocytosis needs to consider the problem of endosomal escape. After genes undergoing endocytosis, endosomes/lysosomes may form, and lysosomes will decompose foreign substances into small molecules for reuse, which will make the therapeutic gene ineffective. Therefore, target genes should escape from endosomes after endocytosis to avoid being degraded.
Generally, cationic polymers mainly escape from endosomes to mediate gene delivery, which is represented by branched polyethyleneimine (bPEI, 25 kb). The bPEI may form PEI-DNA complexes first, enter cells through endocytosis, then escape from the endosome into the cytoplasm through the “proton sponge” effect [51].

2.2.4. Entering the Nucleus

For viral vectors, the virus can accomplish the processes of membrane entry, endosomal escape, and entry into the nucleus only by its shell. The delivery efficiency of non-viral gene delivery methods is generally low. The reason may be that the functionality of non-viral gene delivery materials is not complete. In general, numerous studies of non-viral delivery methods have focused on cytoplasmic membrane penetration and endosomal escape. However, in the whole process of gene delivery, whether the exogenous gene can enter the nucleus for expression stably is one of the key factors affecting the efficiency of gene expression. The nucleus is the centre of the cell surrounded by two membranes, and few small particles can freely pass in and out through the nuclear pores [6].
For dividing cells, gene delivery becomes relatively easy, because during cell division the nuclear envelope breaks, making it easier for foreign genes to enter the nucleus [6]. Studies have shown that low molecular weight bPEI/DNA complexes enter the nucleus more easily than the high molecular weight bPEI/DNA complexes [52]. But for cells without division, gene delivery becomes relatively complicated and difficult, and the nuclear membrane blocks larger-sized molecules, which is one of the major challenges of gene delivery.
For this problem, nuclear localization signal (NLS) peptides [53] were used, which can help larger particles to complete the nuclear entry by embedding nuclear pores in the nuclear envelope. Subsequent studies have shown that binding to NLS polypeptides could improve gene entry and expression in non-dividing cells [6][54].

2.2.5. Material Stability

Skeletal muscle gene delivery requires sufficient material stability in the ECM, and then easily to be degraded or cleared in cells. For cationic gene delivery materials, it is easy to form cationic material/DNA complex, but the cationic complex can electrostatically interact with negatively charged biomacromolecules in the ECM, leading to significantly reduced gene delivery efficiency. Meanwhile, the strong binding of material molecules to DNA does not necessarily improve the transfection efficiency, since it may hinder the unpacking of the cationic material and DNA [55]. For branched PEI, the representative of cationic polymers, high molecular weight polymers can bind to DNA better to protect DNA from degradation, and are more readily taken up by cells, resulting in higher delivery efficiency, but low molecular weight polymers have lower cytotoxicity and better DNA unpacking ability [56][57]. Therefore, it can be speculated that there should be an optimal molecular weight range of polymers, so that these polymers have suitable DNA compression and unpacking ability with better biosafety and gene delivery efficiency as well.

2.2.6. Biosecurity

Although there are many methods with high gene delivery efficiency, there are also biological safety issues, such as cytotoxicity, inflammatory response, and immune reaction. For in vivo gene delivery, biosafety is an unavoidable issue. Although viral vectors have high gene delivery efficiency and expression level, they can easily trigger excessive inflammatory responses [58] or immune reaction, while non-viral delivery methods avoid the occurrence of side effects to a great extent. For cationic polymers, the toxicity mainly comes from excessive positive charges. At present, polyethylene glycol (PEG) has been used to shield the cations on the surface of the complex to reduce cytotoxicity [59]. Grandinetti et al. showed that the polymer could directly participate in the nuclear localization of DNA through its membrane destruction characteristics, which may also be the reason for its cytotoxicity [60]. Therefore, it seems to be a better choice to use neutral block polymers since they are more effective than cationic polymers in skeletal muscle gene delivery [14][18][19][61].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14112428

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