Gene therapy was first introduced as a potential strategy for treating recessive-inherited disorders. This concept centered on the idea of introducing a functional copy of a mutated gene to restore normal cellular function. With a few exceptions, gene therapy has shown success in various applications. However, its primary emphasis has shifted towards targeting acquired diseases, aiming to modify their underlying processes [23••].

Gene therapy can be classified into two main types: somatic and germline. Somatic gene therapy aims to treat patients directly without altering the genetic makeup of their offspring. This involves the introduction of a functional gene into specific cells, thereby correcting the underlying genetic defects. However, it is important to note that even if somatic gene therapy successfully modifies a patient’s genes to address a particular condition, the risk of passing on the ailment to future generations remains. This form of gene therapy is practiced in genetic laboratories worldwide.

In contrast, germline gene therapy involves inserting exogenous genes into cells involved in producing sperm or fertilized eggs. As a result, any genetic modification to these cells can be inherited by the offspring. Although germline gene therapy has the potential to prevent hereditary diseases, it is a highly controversial area of research owing to technical and ethical concerns [24]. Currently, limited research has been conducted in this field.

In addition to these two types, various methods have been employed for gene therapy. These include the direct injection of DNA, liposome-mediated DNA transfer, calcium phosphate transfection, electroporation, the use of retrovirus vectors, site-directed recombination, artificial chromosomes, other viral vectors, targeted gene transfer via receptors, and gene activation with associated activities [25••]. Each method offers unique advantages and considerations depending on the specific goals of the gene therapy intervention.

Studies have shown the use of gene therapy to inhibit nociceptive transmission at the supraspinal level [26••]. Previous experimental studies on gene delivery in the brain have mainly focused on the medulla oblongata, a region responsible for pain control, which presents challenges owing to its proximity to vital organ systems like the pulmonary and cardiovascular. To address this, it may be advantageous to redirect research efforts towards more accessible locations, especially in the context of prevalent conditions associated with chronic pain such as complex regional pain syndrome or fibromyalgia. Targeting various points along the pain pathway is feasible with gene therapy, but particular attention is given to primary afferent neurons (PANs) and their synapses, as well as second-order neurons inside the dorsal horn, owing to their significant involvement in the pathophysiological development of chronic pain [27].

The concept of gene therapy for pain is solely based on the way genes are delivered that encodes the proteins that block the nociceptive receptors or would interfere with the nociceptive molecule inside the functional unit of the brain, so-called neurons. Introduction of certain genes into neurons, where they produce particular proteins, is the basis of gene therapy for persistent neuropathic pain. These proteins act on the ionic channels and receptors implicated in the development of pain due to neuropathy [28••]. This is achieved either by viral method, which is called transfection, or non-viral vector methods known as transduction.

To deliver analgesic genes in the nervous system, three gene therapy approaches have been used: cell-based therapies, which typically involve transplanting mutated cells into the subarachnoid space [29••, 30, 31]; the use of plasmids and oligonucleotides, which are occasionally enclosed in the liposomes to facilitate entry into cells [32–34]; and the use of certain viral-based vectors. The most popular method for delivering genes to the nervous system is viral vector gene therapy, which makes use of viruses’ innate capacity to transmit infection for their genes to be expressed by host cells [35, 36].

It has been previously demonstrated that HSV-based vector-induced transfer of the ENK gene to rodent’s dorsal root ganglia in the lumbar region through footpad inoculation lowers C-fiber-evoked pain responses in reflex to immediate inflammatory stimuli, such as a capsaicin injection [37] or formalin [27], and attune the increased sensitivity to pain related to chronic inflammation [38, 39]. In addition, implementation of the rat vibrissal pad has been shown to reduce neuropathic pain related to trigeminal neuralgia [40]. The method of footpad inoculation has also been shown to abridge nociceptive behavior in mouse or rat models of chronic neuropathic pain that also includes pain due to diabetic neuropathy and spinal nerve ligation [41••, 42••]. Since then, other researchers have demonstrated that visceral pain models of cystitis and pancreatitis have elicited analgesia when ENK-expressing HSV vectors are injected directly into the bladder or pancreas and have their expanded findings to primate models [43–46]. The combination of all these researches was the projections towards the first ever human gene experiment for the management of pain.

In a partial sciatic nerve damage model of neuropathic pain in rodents, McMahon et al. showed that the glial cell line–derived neurotrophic factor (GDNF) direct intrathecal infusion lowered pain and its related behaviors along with ectopic nerve discharges [47]. Multiple studies have demonstrated that administration of the recombinant p75 soluble TNFR (sTNFR) peptide (etanercept) intrathecally depleted mechanical allodynia in a mouse model of neuropathic pain, while counteracting antibodies aimed against the p55 TNF receptor (TNFR) reduced hyperalgesia related to the heat and mechanical allodynia [48–50]. The Watkins group has shown in rat tests that intrathecal mode of injection of adenovirus plus the adeno-associated virus or simple plasmids engineered to produce IL-10 results in the liberation of IL-10 into the cerebrospinal fluid. In prototype of neuropathic pain generated by either nerve compression or injecting allogenic chemicals along the sheath of the nerve, the anti-inflammatory cytokine can either reverse existing neuropathic pain or prevent it from occurring [51–53].

Non-viral vectors are also vital for gene therapy, but there is not much evidence supporting their role in pain management. The efficiency and specificity of non-viral vectors in comparison to viral vectors are lower. Besides the non-viral vector method, there are different ways to deliver gene threads, namely, by polymers that are either biodegradable or non-biodegradable, lipids that are conventional, gemini surfactants, lipidoids, helper lipids, peptides (peptic nucleic acid, polypeptides, functional peptides), inorganic materials such as mesoporous silica nanoparticles, gold nanoparticles, magnetic materials, carbon nanotubes and graphene, quantum dots, and hybrid systems (inorganic-organic, modified PEI, inorganic lipid, and peptide bond).

Gene therapy has its own set of limitations such as dosing, safety, and efficacy, apart from other drawbacks such as the ethical issues of gene therapy, as it will change not only the physical but also the expressive side of a protein to attain a positive result in the process of dealing with chronic pain. Despite the immense potential of gene therapy as a medical treatment, progress in the development of efficient clinical procedures has been gradual. The development of reliable and effective gene delivery devices is an issue. Although gene therapy works well for single-gene problems, additional studies are needed for multiple gene disorders. Although viruses are effective gene carriers, they have certain drawbacks. To improve target specificity and lessen injury to nearby healthy tissues, further research must be done to create novel, efficient gene carriers [25].