Gene therapy uses. Bacterial meningitis is a medical emergency. Its major etiological agents are Streptococcus pneumoniae, Klebsiella pneumonia, and Listeria monocytogenes. As well as, Haemophilus influenzae, and Neisseria meningitidis. But Streptococcus pneumonia and Neisseria meningitidis are the most common and persistent. In fact, the pneumococci are especially so. Children 5 years or less and adults 60 years or more are the most affected by the disease.
Diagnosis using gram staining, culture, is made. Rarely, is molecular and antibody tests used. Such as Polymerase Chain Reaction (PCR) and latex agglutination-based tests. Respectively, antibiotics and corticosteroid are the most widely-used line of treatment. However, antibiotic resistance is emerging to be a serious challenge, especially with pneumococcal meningitis. So, in spite of antibiotics, mortality rates are still up to 34%. And approximately 50% of survivors suffer long-term neurological damage.
Hence, there is an urgent need for a more effective treatment of the disease. The aim of this paper is to discuss how gene therapy could be.
Introduction
Bacterial meningitis is caused by bacterial organisms. This includes Streptococcus pneumoniae, Klebsiella pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and Haemophilus influenzae (Brooks et al., 1980). The disease is primarily managed using antibiotics. In addition to dexamethasone, an anti-inflammatory agent, as an adjunct therapy (de Gans et al., 2002; Odio et al., 1991).
Cases of Haemophilus Influenza meningitis have been on the decline. Cases of pneumococci are gradually becoming the next most important. The major reason for this is the ability of pneumococci to be really persistent in the cerebrospinal fluid. Resulting in higher mortality as well as neurological damage even in survivors (Fiore et al., 200; McCullers et al., 200). Little wonder that 35% of them that cause the disease have been found to be resistant. The antibiotics used in their management (Whitney et al, 2000; Doern et al., 2001; Richter et al., 2002),
As a result, bacterial meningitis has continued to be a huge clinical problem. In fact, despite high antibiotic effectiveness and improved critical care, the disease still accounts for mortality rates as much as 34% (van de Beek et al., 2006). Evidently, emerging antimicrobial resistance is now a serious challenge, prompting the need for novel therapeutic approaches (Stanek et al., 1999) This paper seeks to reveal how gene therapy could be a more viable therapeutic approach for the disease.
Definition
Bacterial meningitis is an acute inflammatory condition of the membranes that surround the brain. In addition to the spinal cord, the meninges, (Sáez-Llorens et al, 2003). Also the parenchyma of the brain itself (Swartz et al., 1984). Meningitis can also be triggered by viral, fungal, non-infectious agents such as drugs and neoplastic diseases (Hoffman et al., 2009).
During bacterial meningitis, there is a migration of highly-activated leukocytes into the subarachnoid space and along the spinal cord, inflammation of the ventricles (ventriculitis) (Kastenbauer et al., 2001), and destruction of hippocampal structures which has been identified as a possible cause of the persistent neuropsychological symptoms characteristic of the disease (Zysk et al., 1996; Nau et al, 199b).
The disease has been recognised for more than 100 years to be caused by the invasion of bacterial organisms into the subarachnoid space, with the arachnoid and the pia mater particularly affected (Flexner, 1907). Bacterial meningitis requires immediate diagnosis, treatment, and care (Hoffman et al., 2009).
Epidemiology
The epidemiology of bacterial meningitis has been evolving over the past decades as a result of the introduction of the use of conjugate vaccines and the preventive antimicrobial treatment of pregnant women (Matthijs et al, 2010). While cases due to Haemophilus influenzae have almost been eradicated, pneumococci still continue to be the most important cause of the disease in children and adults all in the U.S., Europe, and Africa (Adams et al., 1993).
Every year, the incidence varies between 1.1 and 2 in the U.S., (Schuchat et al., 1997; Wenger et al., 1990). In Western Europe (Berg et al., 1996) and as many as 12 in 100,000 in Africa (O’Dempsey et al., 1996). Children younger than 5 years and adults over 60 years are the most susceptible to the disease. According to the CDC, the symptoms of meningitis generally include fever, headache, and stiffness of the neck. In addition to altered consciousness, vomiting, and photophobia. The presence of a rash has been found to specifically indicate bacterial meningitis (van de Beek D et al., 2006).
Current Diagnosis and Management
Diagnosis is the detection of bacteria in CSF. Gram staining or a positive bacterial culture has been cited as the first line of choice (Straus et al., 2006). Other methods include Polymerase Chain Reaction (PCR) (Fox et al., 2007) and latex agglutination-based rapid tests (Hayden et al., 2000). In adults, cranial CT scan accompanied by lumbar puncture has also been used to tremendous success (Hasburn et al., 2001).
Antibiotics and corticosteroids, the preferred treatment modality for the disease, must be instituted immediately after diagnosis. However, the data for treatment durations are very limited and mostly based on expert opinion (Tunkel et al., 2004). Treatments are still often followed by different complications in spite of the adjunct corticosteroid therapy. For example, with pneumococcal meningitis, in spite of therapy, mortality can still be up to 34% (van de Beek et al., 2006) and long-term neurological sequelae in up to 50% of survivors are not uncommon (Weisfelt et al., 2006).
The associated complications and the evidence of increasing resistance of the disease to antibiotic therapy (Fenoll et al., 1991; Marton et al., 1991) occasioned mainly by limited ability to penetrate the CSF and reduced concentration and intrinsic activity in infected fluids (Sande M.A., 1989; Tauber M.G. et al., 1990) have made the need for a more effective treatment modality highly imperative. A highly promising one is gene therapy (van de Beek et al., 2012).
Gene Therapy: What is It?
Also known as human gene transfer, gene therapy is a largely experimental medical field attempting to use and deliver genetic material into patients’ cells for the treatment of diseases (Kaji et al., 2001). Although Martin Cline performed the first attempt at modifying the human DNA in 1980, the first successful such procedure was not done until May 1989 with the approval of the National Institutes of Health (Rosenberg et al., 1990). Between then and 2018, over 2,800 clinical trials were conducted, with more than half of them in Phase 1 (Gene Therapy Clinical Trials Worldwide Database, 2016).
In 1993, the first somatic treatment, with the goal of curing malignant brain tumours using recombinant DNA, that produced a permanent genetic change, was performed (Oldfied et al., 1993). Since, researchers have been making efforts to apply gene therapy to the treatment of a wild range of diseases such as choroideremia and ADA-SCID, among many others (Sheridan C., 2011). In 2003, China approved the first commercial gene therapy, Gendicine, for the treatment of cancers (Pearson et al., 2004).
As evident in the efforts targeted at the eradication of latent HIV reservoirs and the correction of the mutation that causes sickle cell disease, the emergence of the CRISPR gene-editing technology is opening up new possibilities for the application of gene therapy to the treatment of diseases (Gupta et al., 2014; Dever et al., 2016; Bak et al., 2018).
Principles of Gene Therapy for Bacterial Meningitis
The most common form of gene therapy is based on the use of the DNA to encode a functional therapeutic gene for the replacement of a defective gene. For delivery into cells, the DNA molecule is packaged within a vector using techniques such as zinc finger nucleases and CRISPR and incorporated into the chromosomes to knock out and replace the defective genes (Urnov et al., 2010). An alternative way of genetic material delivery is through the use of viruses such as retroviruses, adenoviruses, and herpes simplex (Gene Therapy Clinical Trials Worldwide Database, 2016).
For pneumococcal meningitis, the most fulminant form of bacterial meningitis, a genetic association study has identified a possible new adjunctive treatment based on a genetic variation in the complement factor 5 gene that has been shown to have an unfavourable outcome in the disease (Woehrl et al., 2011). The genetic variation results in increased activation of the complement system (Giles et al., 2015). As a result, it is being extensively targeted and the pathophysiological mechanisms are being identified in order to provide promising leads for future treatments (Kasanmoentalib et al., 2013).
The inhibition of the complement of the factor 5 gene in experimental studies in mouse using antibodies considerably reduced mortality especially when used in conjunction with dexamethasone (Woerhl et al., 2011; Kasanmoentalib, 2015). Thus, the completion of an RCT on C5a antibodies expressed in septic organ dysfunction may possibly be a positive stimulus for the full development of complement inhibition in bacterial meningitis patients.
Possible Complications and Ethical Concerns
Gene therapy is not without possible complications. A trial in France has linked it to the development of leukaemia. This in a patient treated for SCID (Hacein-Bey-Abina S et al, 2002). More work needs to be done to achieve the stable insertion of genes into stem cells. This to prevent tumour-inducing insertional mutagenesis (Sclimenti et al., 2001). Despite coming at a high cost, the therapy has also been found to initiate unintended immune responses. Thereby reducing the effectiveness of repeated treatments (McCain, 2005).
As with other treatment modalities, the medical application of gene therapy is subject to the regulatory oversight of the FDA. But there are concerns that gene therapy products are subjected to greater scrutiny and review before approval by the FDA according to the agency’s well-defined requirements and an Institutional Review Board (U.S. FDA, 1993). The National Institutes of Health (NIH) is the primary regulator of all federally funded gene therapy research in the United States. And the safety of gene therapy has continued to be a subject of increasing interest and concern (Gonin et al., 2005).
Summary
Limited to high and median-income countries, there have been tremendous successes in the management of bacterial meningitis. This is due to the introduction of conjugate vaccines and the adoption of preventive treatment. The global devastating attack rates of the disease and the increasing failure of the available treatment option, empirical antibiotic therapy, due to local drug resistance has called for a novel therapeutic approach.
A strong candidate for that is gene therapy. Since the first successful attempt at modifying the human DNA in 1989, this novel and highly-controversial therapeutic approach has been gaining a lot of interest for the treatment of a wide range of diseases including bacterial meningitis. However, it is not without its hurdles. Gene therapy is expensive. And if the DNA is mistakenly inserted in the wrong genomic spot, a tumour can result. Some vectors can induce toxicity and unintended inflammatory and immune responses. Also, multiple treatments may be needed.
Conclusion
Gene therapy is a viable modality for the treatment of bacterial meningitis. It’s adoption for the disease is pertinent considering the many inadequacies of antibiotic therapy. Adjunctive corticosteroid treatment is currently used for the management of the disease. The grey areas to watch are its potential complications and the regulatory bottlenecks to its use. Apart from those, the prospect remains robust.