**7. Conclusion**

**6.2.** *In vivo* **delivery by nanoparticles**

58 In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

cytotoxic side effects [108, 109].

limited life span are optimal [109].

The *ex vivo* delivery of an HIV gene therapy treatment will only be achievable in developed countries with the appropriate resources to facilitate the approach and this will not be feasible in countries which currently have the largest burden of HIV, such as sub-Saharan Africa. We and others are working on an alternate and highly relevant systemic, *in vivo* approach, which may ultimately be accessible to all. This approach utilises nanotechnology to deliver the HIV therapeutic to target cells, ideally those of the latent reservoir. According to the Recommendation of the European Commission in 2011 the currently accepted definition of a nanoparticle (NP) is a particle where one or more external dimensions is in the size range of 1 to 100 nm [107]. However, larger particles with sizes up 1000 and 2000 nanometres are commonly referred to as 'nano', especially since for medical purposes the size range of ≤100 nm is not always practical, as a larger surface can carry more drug on a single particle [108, 109]. However, to be able to be used in the human body, NPs must be biocompatible and without

Concentrating on HIV drug delivery, NPs have the unique feature of being able to absorb and carry other compounds on their relatively large functional surface [109]. Using NPs as delivery agents has the potential advantages of highly specific and controlled drug delivery to a targeted tissue or cell, such as those of the latent reservoir, keeping non-target organs and cells free of the drug, thereby reducing toxicity. Further, by releasing the drug in a controlled manner at a predetermined rate, achieved through changes in the physiological environment like pH, temperature or enzymatic activity, the resulting therapeutic efficacy can be increased [108–110]. Importantly, nano-based delivery systems have been shown to transport therapeutics across the blood-brain barrier, which is highly relevant for treating neuro-degenerative diseases and specifically the HIV reservoir in the central nervous system [111]. Prior to use of NPs in humans, the following basic prerequisites need to be known: drug incorporation and release, formulation stability and shelf life, biocompatibility, biodistribution and targeting, potential toxicities as well as functionality [109]. Another consideration are the possible adverse effects of residual material after drug delivery, therefore biodegradable NPs with a

There are many types of NPs reported as delivery vehicles for HIV therapeutics, such as liposomes, micelles, polymer capsules, inorganic gold particles and dendrimers [112]. The number of different formulations of NPs being explored for HIV and other diseases is steadily increasing and a focused review on nanoparticle systems is provided by Pelaz et al. [112]. An

In the case of HIV, NPs have been used to deliver antiretroviral drugs or anti-HIV therapeutics, such as siRNAs. Inorganic gold particles delivering antiretrovirals have progressed through to *in vivo* delivery in mouse models, as have poly(amidoamine) PAMAM dendrimers and RNA-aptamer conjugates (as previously describes in Section 3.2.2.2), that deliver a combination of anti-HIV siRNAs. The gold particles and PAMAM dendrimer nano-platforms will

The NP platforms delivering an antiretroviral drug were comprised of inorganic gold nanoparticles particles (AuNPs) ~2–10 nanometers in diameter and were conjugated with an HIV integrase inhibitor, raltegravir [113]. Modification of raltegravir was necessary to link the inhibitor

be discussed below to highlight the challenges of targeting the HIV latent reservoir.

example of the *in vivo* gene therapy process is depicted in **Figure 4**.

The field of HIV gene therapy is rapidly evolving, with development of both novel anti-HIV therapeutics and delivery systems to ensure cell specific targeting. While an *ex vivo* gene therapy approach for HIV is well on the path to patient translation, further targeting of the latent reservoir will be necessary to achieve a systemic, *in vivo* gene therapy approach. This will require identification of biomarker/s for latently-infected cells and novel ways to incorporate them into viral vectors and/or nanoparticle platforms. Once achieved, the next challenge will be the cost of treatment, which is becoming a driving factor in the context of HIV, as the global burden of HIV is predominantly in sub-Saharan Africa. The cost of *ex vivo* gene therapy approaches is prohibitive in developing countries and *in vivo* nanoparticle approaches, whilst more cost effective, do not yet achieve sustained virus remission. Further optimisation and refinement of current delivery systems is required to enable wide scale application of a functional HIV cure.

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