Gene Therapy for Rheumatoid Arthritis

Adam Reinhardt; Raphael Hirsch

Future Rheumatol. 2007;2(4):403-413.

Abstract and Introduction

Abstract

Therapy for rheumatoid arthritis (RA) has seen significant advances over the past decade. The use of biologic agents, such as TNF-α inhibitors, have led to improvement in up to 60% of RA patients. Unfortunately, biologic therapy also presents significant limitations, including systemic side effects, a short half-life with requirement for frequent dosing, and a lack of curative response. Owing to such limitations, the ideal therapy for RA remains unrealized. Progress in the field of gene therapy provides interesting and applicable methods to overcome many of these deficits. In this review we will discuss some of these advances, focusing on the development of new vectors, gene-therapy targets and regulatory mechanisms. With continued efforts in this field, the hope for a lasting, regulated and possibly curative modality appears attainable.

Introduction

Arthritis is the leading cause of disability in the USA, affecting one out of five (46 million) adults.^[201] Rheumatoid arthritis (RA), a chronic, destructive inflammatory arthritis, is a major subtype with a worldwide prevalence ranging from 0.2% to greater than 1% in North America.^[1] Advances in understanding the pathophysiology of RA have led to the development of novel therapeutic biologic agents, such as TNF-α and IL-1 inhibitors. Importantly, these treatments have demonstrated efficacy in 60% of RA patients.^[2] Despite the many benefits of these systemic agents, their side effects, short duration of effect, need for long-term treatment and inability to cure the disease, cause them to fall short of optimal RA therapy. For these reasons, the development of targeted gene therapy is an increasingly attractive option for long-term RA disease control. In order to make gene therapy a viable therapeutic option for RA the following need to be optimized: gene-delivery, vectors, candidate molecules and targets and methods to regulate transgene expression.

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Table 1. Rheumatoid Arthritis Gene Therapy Targets Listed With Associated Vectors and Therapeutic Transgenes
Therapeutic approach	Targets	Transgene	Vectors used (Ref.)	Findings
Inflammatory cytokine inhibition	TNF	sTNFR	AAV^[34]	Decreased inflammation and bone/cartilage destruction
		sTNFR-IgG	Plasmid^[26]
	IL-1	sIL-1R-Ig	Ad^[35]
		IL-1Ra	Ad^[35]
			RVs^[39,40]
	IL-18	IL-18 bp	rAAV^[41]
			Ad^[44]
		IL-18	Ad^[43]	Increased bone and cartilage destruction
	IL-17	IL-17	Ad^[42]
Inhibitory cytokines	IL-4	IL-4	Ad^[49,52,53]	CIA suppression and cartilage protection
	IL-10	IL-10	AAV^[50]
	IL-13	IL-13	Ad^[46,47,48]
			RV^[56]
			Plasmid^[27]
			Ad^[57,58]
T-cell inhibition	T cells	CTLA-4Ig	Ad^[62]	CIA suppression
Pannus formation	Apoptosis	Fas-L	Ad^[69]	FLS apoptosis-sparing chondrocytes
		FADD	Ad^[72]
		TRAIL	Ad^[70]
		p53	Ad^[73]
		PUMA	Plasmid^[74]
		p21	Ad^[75,103]	Inhibited FLS migration, CIA suppression
		STAT3	RV^[76]	FLS apoptosis
	Angiogenesis	Endostatin	LV^[87]	Suppression of TNF-induced arthritis
		Angiostatin	RV^[84]	CIA suppression
			HIV^[85]
			AAV^[86]
		sVEGFR	Ad^[90]	CIA suppression
Intracellular signaling	NF-κB	IκBα	Ad^[78]	Inhibition of NF-κB
		NF-κB decoy ODN	Liposome^[81]
		IKKκBdn	Ad^[82]	CIA suppression
			AAV^[83]	CIA suppression
Cartilage and bone destruction	MMP	RzMMP1	RV^[94]	Decreased FLS invasiveness
		TIMP1 and 3	Ad^[96]	Decreased cartilage destruction by FLS
		MMP1 antisense	RV^[95]

AAV = Adeno-associated virus; Ad = Adenovirus; CIA = Collagen-induced arthritis; CTLA = Cytotoxic T-lymphocyte antigen; FADD = Fas-associated death domain; FAS-L = Fas ligand; FLS = Fibroblast-like synoviocytes; IKKk-dn = Inhibitor of NF-kB kinase b; IL1-Ra = IL-1-receptor antagonist; MMP = Matrix metalloproteinase; NF-kB = Nuclear factor-kB; ODN = Oligodeoxynucleotide; PUMA = p-53-upregulated modulator of apoptosis; rAAV = Recombinant AAV; RV = Retrovirus; RzMMP1 = MMP-1-specific ribozymes; STAT = Signal transducer and activator of transcription; TIMP = Tissue-specific inhibitors of MMPs; TNFR = TNF receptor; TRAIL = TNF-related apoptosis-inducing ligand; VEGFR = VEGF receptor.

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