Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

Abstract

Gene transfer has long been a compelling yet elusive therapeutic modality. First mainly considered for rare inherited disorders, gene therapy may open treatment opportunities for more challenging and complex diseases such as Alzheimer's or Parkinson's disease. Today, examples of striking clinical proof of concept, the first gene therapy drugs coming onto the market, and the emergence of powerful new molecular tools have broadened the number of avenues to target neurological disorders but have also highlighted safety concerns and technology gaps. The vector of choice for many nervous system targets currently is the adeno-associated viral (AAV) vector due to its desirable safety profile and strong neuronal tropism. In aggregate, the clinical success, the preclinical potential, and the technological innovation have made therapeutic AAV drug development a reality, particularly for nervous system disorders. Here, we discuss the rationale, opportunities, limitations, and progress in clinical AAV gene therapy.

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

“…Over the past decade AAV-based therapies have shown numerous successes from proof of concept to clinical trials in genetic diseases [17,27]. These studies have also identified off-targets transduction and humoral immune response against the vector as the two main serious obstacles that hinder successful AAV-based therapies in patients [39,61].…”

“…Nevertheless, currently, in vivo gene therapy assays mostly use adeno-associated virus (AAV)-based strategies as these vectors do not integrate the genome of transduced cells, spread more easily in the tissues and display a limited immunogenicity [9]. AAV serotypes 2/9 and 2/rh10 are commonly used to transduce the central nervous system and several clinical trials are ongoing with promising results [17,27]. Moreover, an AAV9-based therapy recently obtained market authorization from FDA to treat spinal motor atrophy in infants [38].…”

Towards the optical cochlear implant: optogenetic approaches for hearing restoration

“…AAVs appear to be highly promising candidates, since they have little potential for virus-related harm in the transduced tissue, while being characterized by an intrinsically high neural tropism, long-term availability of the desired transgene, and high expression levels (Willett & Bennett, 2013;Ahmed et al, 2017;Hudry & Vandenberghe, 2019;Lotfinia et al, 2019). Experimentally, AAVs have been used in several studies to genetically restore auditory function, and even reached clinical trials for the treatment of various other disorders, including retinal dysfunction (Akil et al, 2012;Askew et al, 2015;Landegger et al, 2017;Pan et al, 2017;Suzuki et al, 2017;Al-Moyed, 2019;Hudry & Vandenberghe, 2019;Lotfinia et al, 2019). In fact, a first AAV-mediated gene therapy for vision restoration (Luxturna) has recently been FDA-approved (Keeler & Flotte, 2019;Lotfinia et al, 2019).…”

Optogenetic and chemogenetic therapies for epilepsy

“…Vectors differ depending on whether they carry DNA or RNA with a reverse transcriptase and on their capsid/envelope (Hudry and Vandenberghe, 2019). Early viral vectors were derived from adenoviruses which can carry a large amount of genetic material, but the adenovirus capsid is particularly immunogenic, contributing to adverse events in clinical trials (Wilson, 2009).…”