This article provides insights into evolution of route of administration (RoA) in AAV gene therapy clinical trials. It is based on a comprehensive analysis of clinical trials initiated since 2003 through January 2019. We discuss all indications and therapeutic areas, but call out separately neurology/ neuromuscular and ophthalmology. You can find complete dataset in our Store.

The number of gene therapy (GTx) clinical trials has increased drastically since 2003. Clinical programs have evolved with scientific knowledge and clinical experience. Here, we discuss evolution of Route of Administration (RoA) for AAV GTx in clinical trial settings. RoA is trivial for some indications. For example, intravenous RoA is used for hematologic and some metabolic conditions. In contrast, AAV constructs for neurological, neuromuscular, and ocular disorders may be delivered via variety of routes.

Route of Administration: Neurology and neuromuscular disorders

• For simplicity, we discuss five types of RoA, including
• BS – via brain surgery (for example, 6 burr hole method),
• IV – intravenous,
• IT – intrathecal,
• IC – intracisternal,
• IM – intramuscular.

Figure 1 shows RoA evolution for trials initiated between 2003 and 2018.


Direct targeting an affected organ or tissue has been an obvious first choice. Therefore, up until 2013, clinical trials utilized exclusively neurosurgical approaches to inject AAV GTx constructs into the brains of patients with neurological disorders. Examples include Alzheimer’s, CLN2, Parkinson’s, and MPS3A diseases. Usually, brain surgery is required to give intraparenchymal or intraventricular injections.

For several CNS indications, direct-to-CNS intrathecal (IT) or intracisternal (IC) RoAs are becoming more preferable due to lower invasiveness. However, AAV GTx administered IT or IC do not always reach the right cells in the brain.

Not surprisingly, intramuscular injections have been used for neuromuscular disorders such as DMD and LGMD.

Intravenous Route in Neurology and Neuromuscular

Today, intravenous RoA dominates neurological and neuromuscular trials (Figure 1). Scientific, clinical, and commercial reasons may explain this trend.

• The ability of certain AAV serotypes to cross the blood brain barrier (BBB) ensures that a portion of therapy reaches the CNS.
• In case of multi-organ disorders, several organs and tissues could be affected with one injection.
• Less invasive administration has clinical appeal for patients and healthcare providers.

However, intravenous administration has its drawbacks. The convenience of IV RoA usually comes with a cost – IV administration requires a much higher dose compared to administration into the CNS or the eye. In turn, higher doses may have the following implications.

• High doses lead to high cost of goods. Historically, cost of goods has not been a significant concern for the pharmaceutical industry. However, for the field of gene and cell therapy, COGS is a critical consideration. COGS consideration is especially important for adult patients because IV dose scales with patient weight.
• Demand higher levels of manufacturing capacity and reproducibility.
• May lead to prohibiting immune response.

For example, spinal muscular atrophy (SMA) type 1 has been an optimal indication for IV RoA. In SMA1 clinical trials, affected babies required much smaller doses compared to what would be needed for adults.

Implications for Clinical Translation

At BioHeights, we work with both biopharmaceutical companies and academic investigators. Often, academic investigators developing AAV GTx have bigger fish to fry than worry about clinical RoA. We recommend that PIs looking to translate their technologies take into account feasibility of RoA. Specifically, RoA considerations are important to inform alternative experimental designs, IND-enabling studies, and clinical protocols. Additionally, effective and appropriate RoA may increase probability of clinical and commercials success of an AAV GTx product, while inappropriate RoA may halt translation. Several simple considerations include:

• Severity of disease: the less severe the disease, the less justifiable an invasive RoA becomes.
• Since IV doses are costly for larger patients, expected clinical benefit should justify the cost.
• In certain diseases, meaningful therapeutic benefit may be attained even if a low percentage of AAV GTx product crosses BBB.

Ophthalmology

In ocular disorders, AAV gene therapy route of administration has included intravitreal (IVT) and subretinal (SR). Figure 2 summarizes RoA used in clinical trials for ocular disorders since 2003. In certain cases, the nature of the disease dictates the RoA. For example, XLRS requires IVT RoA and is not amenable to SR. In case of age-related macular degeneration (AMD), both RoAs could be clinically acceptable. Often, the choice is dictated by desired level of efficacy and convenience.

Figure 2: RoA in clinical trials for ocular diseases.

IVT: intravitreal; SR: subretinal; LHON: Leber hereditary optic neuropathy; RP: retinitis pigmentosa; XLRS: x-linked retinoschisis; AMD: age-related macular degeneration; LCA: Leber congenital amaurosis.

Figure 3 shows that both IVT and SR RoAs have been explored for neovascular (wet) and dry AMD by various sponsors since 2010.

Figure 3: Timeline of initiated wet and dry AMD clinical trials by RoA and sponsor.

IVT: intravitreal; SR: subretinal

Other disease areas

Outside CNS and eye, clinical trials for most other diseases utilize IV, IM, or site-specific route of administration. Table 1 summarizes RoAs for clinical trials initiated between 2003 and 2018.

If you are interested in the entire dataset of clinical trials and corresponding RoAs, please check out our downloadable file in Store. Also, we provide significant discount for current and former BioHeights clients, as well as non-profit and academic organizations.

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Disclaimer: This article is based on publicly available information ONLY. Information is sourced from clinicaltrials.gov, 10k filings, company websites, press releases, peer review publications. Information presented here is not a legal advice. It is simply the author’s opinion and insight based on the publicly available information.