CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood-Brain Barrier and Towards Specific Cellular Targeting.

Nucleic acid-based therapeutic molecules including small interfering RNA (siRNA), microRNA(miRNA), antisense oligonucleotides (ASOs), messenger RNA (mRNA), and DNA-based gene therapy have tremendous potential for treating diseases in the central nervous system (CNS). However, achieving clinically meaningful delivery to the brain and particularly to target cells and sub-cellular compartments is typically very challenging. Mediating cell-specific delivery in the CNS would be a crucial advance that mitigates off-target effects and toxicities. In this review, we describe these challenges and provide contemporary evidence of advances in cellular and sub-cellular delivery using a variety of delivery mechanisms and alternative routes of administration, including the nose-to-brain approach. Strategies to achieve subcellular localization, endosomal escape, cytosolic bioavailability, and nuclear transfer are also discussed. Ultimately, there are still many challenges to translating these experimental strategies into effective and clinically viable approaches for treating patients.

RVG Peptide-Functionalized Favipiravir Nanoparticle Delivery System Facilitates Antiviral Therapy of Neurotropic Virus Infection in a Mouse Model.

Neurotropic viruses severely damage the central nervous system (CNS) and human health. Common neurotropic viruses include rabies virus (RABV), Zika virus, and poliovirus. When treating neurotropic virus infection, obstruction of the blood-brain barrier (BBB) reduces the efficiency of drug delivery to the CNS. An efficient intracerebral delivery system can significantly increase intracerebral delivery efficiency and facilitate antiviral therapy. In this study, a rabies virus glycopeptide (RVG) functionalized mesoporous silica nanoparticle (MSN) packaging favipiravir (T-705) was developed to generate T-705@MSN-RVG. It was further evaluated for drug delivery and antiviral treatment in a VSV-infected mouse model. The RVG, a polypeptide consisting of 29 amino acids, was conjugated on the nanoparticle to enhance CNS delivery. The T-705@MSN-RVG caused a significant decrease in virus titers and virus proliferation without inducing substantial cell damage in vitro. By releasing T-705, the nanoparticle promoted viral inhibition in the brain during infection. At 21 days post-infection (dpi), a significantly enhanced survival ratio (77%) was observed in the group inoculated with nanoparticle compared with the non-treated group (23%). The viral RNA levels were also decreased in the therapy group at 4 and 6 dpi compared with that of the control group. The T-705@MSN-RVG could be considered a promising system for CNS delivery for treating neurotropic virus infection.

Brain delivery of antidotes by polymeric nanoparticles.

Accidental intoxications from environmental pollutants, as well as intentional self- and chemical warfare-related poisonings affect millions of people worldwide each year. While many toxic agents can readily enter the central nervous system (CNS), the blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. Consequently, poisoning antidotes usually cannot reach their site of action in the CNS in therapeutically relevant concentrations, and thus only provide effective protection to the peripheral nervous system. This limitation can be overcome by encapsulating the antidotes in nanoparticles (NP), which can enhance their CNS accumulation without damaging the integrity of the BBB. Among nanocarriers, polymer-based drug delivery systems exhibit remarkable benefits, such as bioavailability, cell uptake and tissue retention. Furthermore, due to their capacity to mask unfavorable physicochemical properties of cargo drugs, polymeric NPs were able to improve BBB transport of various pharmaceuticals. However, while polymer NP-mediated treatment of various pathological brain conditions, such as glioma and Alzheimer's disease were exhaustively studied, the application of polymeric nanocarriers for brain-targeted delivery of antidote molecules has not been adequately examined. To display its therapeutic potential, we review the state of the art of polymer NP-assisted CNS delivery of antidotes for various poisonings, including heavy metal and organophosphorus intoxications.

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to death receptors. However, the blood-brain barrier (BBB) is a major obstacle for these biologics to enter the central nervous system (CNS). We therefore investigated if antibody-based fusion proteins that combine hexavalent TRAIL and angiopep-2 (ANG2) moieties can be developed, with ANG2 promoting receptor-mediated transcytosis (RMT) across the BBB. We demonstrate that these fusion proteins retain the potent apoptosis induction of hexavalent TRAIL-receptor agonists. Importantly, blood-brain barrier cells instead remained highly resistant to this fusion protein. Binding studies indicated that ANG2 is active in these constructs but that TRAIL-ANG2 fusion proteins bind preferentially to BBB endothelial cells via the TRAIL moiety. Consequently, transport studies indicated that TRAIL-ANG2 fusion proteins can, in principle, be shuttled across BBB endothelial cells, but that low TRAIL receptor expression on BBB endothelial cells interferes with efficient transport. Our work therefore demonstrates that TRAIL-ANG2 fusion proteins remain highly potent in inducing apoptosis, but that therapeutic avenues will require combinatorial strategies, such as TRAIL-R masking, to achieve effective CNS transport.

Use of Biodegradable, Chitosan-Based Nanoparticles in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 24 million people worldwide and represents an immense medical, social and economic burden. While a vast array of active pharmaceutical ingredients (API) is available for the prevention and possibly treatment of AD, applicability is limited by the selective nature of the blood-brain barrier (BBB) as well as by their severe peripheral side effects. A promising solution to these problems is the incorporation of anti-Alzheimer drugs in polymeric nanoparticles (NPs). However, while several polymeric NPs are nontoxic and biocompatible, many of them are not biodegradable and thus not appropriate for CNS-targeting. Among polymeric nanocarriers, chitosan-based NPs emerge as biodegradable yet stable vehicles for the delivery of CNS medications. Furthermore, due to their mucoadhesive character and intrinsic bioactivity, chitosan NPs can not only promote brain penetration of drugs via the olfactory route, but also act as anti-Alzheimer therapeutics themselves. Here we review how chitosan-based NPs could be used to address current challenges in the treatment of AD; with a specific focus on the enhancement of blood-brain barrier penetration of anti-Alzheimer drugs and on the reduction of their peripheral side effects.

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease.

Lafora disease (LD) is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called Lafora bodies (LBs). Delivery of protein-based therapeutics to the central nervous system (CNS) for the clearance of LBs remains a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on the efficacy and CNS delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase, in a mouse model of LD. An enzyme-linked immunosorbent assay has been developed to detect VAL-0417 post-treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using this method, we measured biodistribution in different methods of delivery. We found that intracerebroventricular administration provided robust CNS delivery when compared to intrathecal administration. These data define critical steps in the translational pipeline of VAL-0417 for the treatment of LD.

CNS delivery of targeted protein degraders.

Heterobifunctional small molecule degraders are a subset of targeted protein degraders (TPDs), consisting of two ligands joined by a linker to induce proteasomal degradation of a target protein. As compared to traditional small molecules these compounds generally demonstrate inflated physicochemical properties, which may require innovative formulation strategies to enable their delivery and exert pharmacodynamic effect. The blood brain barrier (BBB) serves an essential function in human physiology, but its presence requires advanced approaches for treating central nervous system (CNS) diseases. By integrating emerging modalities like TPDs with conventional concepts of drug delivery, novel strategies to overcome the BBB can be developed. Amongst the available routes, lipid and polymer-based long-acting delivery seems to be the most amenable to TPDs, due to their ability to encapsulate lipophilic cargo and potential to be functionalized for targeted delivery. Another key consideration will be understanding E3 ligase expression in the different regions of the brain. Discovery of new brain or CNS disease specific E3 ligases could help overcome some of the barriers currently associated with CNS delivery of TPDs. This review discusses the current strategies that exist to overcome and improve therapeutic delivery of TPDs to the CNS.

Minimally invasive nasal infusion (MINI) approach for CNS delivery of protein therapeutics: A case study with ovalbumin.

One of the primary obstacles in treating central nervous system (CNS) disorders lies in the limited ability of disease-modifying drugs to cross the blood-brain barrier (BBB). Our previously described Minimally Invasive Nasal Depot (MIND) technique has proven successful in delivering various drugs to the brain in rat models via a trans-olfactory mucosal approach. In this study, we introduce a novel Minimally Invasive Nasal Infusion (MINI) delivery approach for administering ovalbumin, a model protein, utilizing a programmable infusion pump (iPRECIO SMP-310R) in a mouse model. This research highlights the significant role of olfactory mucosa in nose-to-brain delivery, with an efficacy of nearly 45% compared to intracerebroventricular (ICV) administration. This demonstrates its potential as an alternative procedure for treating CNS diseases, offering a greater safety profile relative to the highly invasive clinical routes traditionally adopted for CNS drug delivery.

Intranasal Nose-to-Brain Drug Delivery via the Olfactory Region in Mice: Two In-Depth Protocols for Region-Specific Intranasal Application of Antibodies and for Expression Analysis of Fc Receptors via In Situ Hybridization in the Nasal Mucosa.

A region-specific catheter-based intranasal administration method was successfully developed, established, and validated as reported previously. By using this method, drugs can be applicated specifically to the olfactory region. Thereby, intranasally administered drugs could be delivered via neuronal connections to the central nervous system. Here, we present a detailed protocol with a step-by-step procedure for nose-to-brain delivery via the olfactory mucosa.Fc receptors such as the neonatal Fc receptor (FcRn) and potentially Fcγ receptor IIb (FcγRIIb) are involved in the uptake and transport of antibodies via the olfactory nasal mucosa. To better characterize their expression levels and their role in CNS drug delivery via the nose, an in situ hybridization (ISH) protocol was adapted for nasal mucosa samples and described in abundant details.

Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease.

Autosomal dominant Alzheimer's disease (ADAD) is a rare early-onset form of Alzheimer's disease, caused by dominant mutations in one of three genes: presenilin 1, presenilin 2, and amyloid ß precursor protein (APP). Mutations in the presenilin 1 gene (PSEN1) account for the majority of cases, and individuals who inherit a single-mutant PSEN1 allele go on to develop early-onset dementia, ultimately leading to death. The presenilin 1 protein (PS1) is the catalytic subunit of the γ-secretase protease, a tetrameric protease responsible for cleavage of numerous transmembrane proteins, including Notch and the APP. Inclusion of a mutant PS1 subunit in the γ-secretase complex leads to a loss of enzyme function and a preferential reduction of shorter forms of Aß peptides over longer forms, an established biomarker of ADAD progression in human patients. In this study, we describe the development of a gene therapy vector expressing a wild-type (WT) copy of human PSEN1 to ameliorate the loss of function associated with PSEN1 mutations. We have carried out studies in mouse models using a recombinant AAV9 vector to deliver the PSEN1 gene directly into the central nervous system (CNS) and shown that we can normalize γ-secretase function and slow neurodegeneration in both PSEN1 conditional knockout and PSEN1 mutant knockin models. We have also carried out biodistribution studies in nonhuman primates (NHPs) and demonstrated the ability to achieve broad PS1 protein expression throughout the cortex and the hippocampus, two regions known to be critically involved in ADAD progression. These studies demonstrate preclinical proof of concept that expression of a WT human PSEN1 gene in cells harboring a dominant PSEN1 mutation can correct the γ-secretase dysfunction. In addition, direct administration of the recombinant AAV9 into the NHP brain can achieve broad expression at levels predicted to provide efficacy in the clinic.

Partial restoration of brain dystrophin by tricyclo-DNA antisense oligonucleotides alleviates emotional deficits in mdx52 mice.

The mdx52 mouse model recapitulates a frequent mutation profile associated with brain involvement in Duchenne muscular dystrophy. Deletion of exon 52 impedes expression of two dystrophins (Dp427, Dp140) expressed in brain, and is eligible for therapeutic exon-skipping strategies. We previously showed that mdx52 mice display enhanced anxiety and fearfulness, and impaired associative fear learning. In this study, we examined the reversibility of these phenotypes using exon 51 skipping to restore exclusively Dp427 expression in the brain of mdx52 mice. We first show that a single intracerebroventricular administration of tricyclo-DNA antisense oligonucleotides targeting exon 51 restores 5%-15% of dystrophin protein expression in the hippocampus, cerebellum, and cortex, at stable levels between 7 and 11 week after injection. Anxiety and unconditioned fear were significantly reduced in treated mdx52 mice and acquisition of fear conditioning appeared fully rescued, while fear memory tested 24 h later was only partially improved. Additional restoration of Dp427 in skeletal and cardiac muscles by systemic treatment did not further improve the unconditioned fear response, confirming the central origin of this phenotype. These findings indicate that some emotional and cognitive deficits associated with dystrophin deficiency may be reversible or at least improved by partial postnatal dystrophin rescue.

Networking to Optimize Dmd exon 53 Skipping in the Brain of mdx52 Mouse Model.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt the open reading frame and thus prevent production of functional dystrophin proteins. Recent advances in DMD treatment, notably exon skipping and AAV gene therapy, have achieved some success aimed at alleviating the symptoms related to progressive muscle damage. However, they do not address the brain comorbidities associated with DMD, which remains a critical aspect of the disease. The mdx52 mouse model recapitulates one of the most frequent genetic pathogenic variants associated with brain involvement in DMD. Deletion of exon 52 impedes expression of two brain dystrophins, Dp427 and Dp140, expressed from distinct promoters. Interestingly, this mutation is eligible for exon skipping strategies aimed at excluding exon 51 or 53 from dystrophin mRNA. We previously showed that exon 51 skipping can restore partial expression of internally deleted yet functional Dp427 in the brain following intracerebroventricular (ICV) injection of antisense oligonucleotides (ASO). This was associated with a partial improvement of anxiety traits, unconditioned fear response, and Pavlovian fear learning and memory in the mdx52 mouse model. In the present study, we investigated in the same mouse model the skipping of exon 53 in order to restore expression of both Dp427 and Dp140. However, in contrast to exon 51, we found that exon 53 skipping was particularly difficult in mdx52 mice and a combination of multiple ASOs had to be used simultaneously to reach substantial levels of exon 53 skipping, regardless of their chemistry (tcDNA, PMO, or 2'MOE). Following ICV injection of a combination of ASO sequences, we measured up to 25% of exon 53 skipping in the hippocampus of treated mdx52 mice, but this did not elicit significant protein restoration. These findings indicate that skipping mouse dystrophin exon 53 is challenging. As such, it has not yet been possible to answer the pertinent question whether rescuing both Dp427 and Dp140 in the brain is imperative to more optimal treatment of neurological aspects of dystrophinopathy.

Investigating the Impact of Delivery Routes for Exon Skipping Therapies in the CNS of DMD Mouse Models.

Nucleic acid-based therapies have demonstrated great potential for the treatment of monogenetic diseases, including neurologic disorders. To date, regulatory approval has been received for a dozen antisense oligonucleotides (ASOs); however, these chemistries cannot readily cross the blood-brain barrier when administered systemically. Therefore, an investigation of their potential effects within the central nervous system (CNS) requires local delivery. Here, we studied the brain distribution and exon-skipping efficacy of two ASO chemistries, PMO and tcDNA, when delivered to the cerebrospinal fluid (CSF) of mice carrying a deletion in exon 52 of the dystrophin gene, a model of Duchenne muscular dystrophy (DMD). Following intracerebroventricular (ICV) delivery (unilateral, bilateral, bolus vs. slow rate, repeated via cannula or very slow via osmotic pumps), ASO levels were quantified across brain regions and exon 51 skipping was evaluated, revealing that tcDNA treatment invariably generates comparable or more skipping relative to that with PMO, even when the PMO was administered at higher doses. We also performed intra-cisterna magna (ICM) delivery as an alternative route for CSF delivery and found a biased distribution of the ASOs towards posterior brain regions, including the cerebellum, hindbrain, and the cervical part of the spinal cord. Finally, we combined both ICV and ICM injection methods to assess the potential of an additive effect of this methodology in inducing efficient exon skipping across different brain regions. Our results provide useful insights into the local delivery and associated efficacy of ASOs in the CNS in mouse models of DMD. These findings pave the way for further ASO-based therapy application to the CNS for neurological disease.

Traumatic brain injury and the development of parkinsonism: Understanding pathophysiology, animal models, and therapeutic targets.

The clinical translation of therapeutic approaches to combat debilitating neurodegenerative conditions, such as Parkinson's disease (PD), remains as an urgent unmet challenge. The strong molecular association between the pathogenesis of traumatic brain injury (TBI) and the development of parkinsonism in humans has been well established. Therefore, a lot of ongoing research aims to investigate this pathology overlap in-depth, to exploit the common targets of TBI and PD for development of more effective and long-term treatment strategies. This review article intends to provide a detailed background on TBI pathophysiology and its established overlap with PD with an additional emphasis on the recent findings about their effect on perivascular clearance. Although, the traditional animal models of TBI and PD are still being considered, there is a huge focus on the development of combinatory hybrid animal models coupling concussion with the pre-established PD models for a better recapitulation of the human context of PD pathogenesis. Lastly, the therapeutic targets for TBI and PD, and the contemporary research involving exosomes, DNA vaccines, miRNA, gene therapy and gene editing for the development of potential candidates are discussed, along with the recent development of lesser invasive and promising central nervous system (CNS) drug delivery strategies.

Nucleic acid therapies for CNS diseases: Pathophysiology, targets, barriers, and delivery strategies.

Nucleic acid therapeutics have emerged as one of the very advanced and efficacious treatment approaches for debilitating health conditions, including those diseases affecting the central nervous system (CNS). Precise targeting with an optimal control over gene regulation confers long-lasting benefits through the administration of nucleic acid payloads via viral, non-viral, and engineered vectors. The current review majorly focuses on the development and clinical translational potential of non-viral vectors for treating CNS diseases with a focus on their specific design and targeting approaches. These carriers must be able to surmount the various intracellular and extracellular barriers, to ensure successful neuronal transfection and ultimately attain higher therapeutic efficacies. Additionally, the specific challenges associated with CNS administration also include the presence of blood-brain barrier (BBB), the complex pathophysiological and biochemical changes associated with different disease conditions and the existence of non-dividing cells. The advantages offered by lipid-based or polymeric systems, engineered proteins, particle-based systems coupled with various approaches of neuronal targeting have been discussed in the context of a variety of CNS diseases. The possibilities of rapid yet highly efficient gene modifications rendered by the breakthrough methodologies for gene editing and gene manipulation have also opened vast avenues of research in neuroscience and CNS disease therapy. The current review also underscores the extensive scientific efforts to optimize specialized, efficacious yet non-invasive and safer administration approaches to overcome the therapeutic delivery challenges specifically posed by the CNS transport barriers and the overall obstacles to clinical translation.

Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production.

Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector.

Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain.

The limitations of central nervous system (CNS) drug delivery conferred by the blood-brain barrier (BBB) have been a significant obstacle in the development of large molecule therapeutics for CNS disease. Though significantly safer than direct CNS administration via intrathecal (IT) or intracerebroventricular (ICV) injection, the topical intranasal delivery of CNS therapeutics has failed to become clinically useful due to a variety of practical and physiologic drawbacks leading to high dose variability and poor bioavailability. This study describes the minimally invasive nasal depot (MIND) technique, a novel method of direct trans-nasal CNS drug delivery which overcomes the dosing variability and efficiency challenges of traditional topical trans-nasal, trans-olfactory strategies by delivering the entire therapeutic dose directly to the olfactory submucosal space. We found that the implantation of a depot containing an AntagoNAT (AT) capable of de-repressing brain derived neurotrophic factor (BDNF) expression enabled CNS distribution of ATs with significant and sustained upregulation of BDNF with efficiencies approaching 40% of ICV delivery. As the MIND technique is derived from common outpatient rhinological procedures routinely performed in Ear, Nose and Throat (ENT) clinics, our findings support the significant translational potential of this novel minimally invasive strategy as a reliable therapeutic delivery approach for the treatment of CNS diseases.

A biocompatible and injectable hydrogel to boost the efficacy of stem cells in neurodegenerative diseases treatment.

AIMS: Stem cell therapies emerged as treatment modalities with potential to cure neurodegenerative diseases (NDs). However, despite high expectations, their clinical use is still limited. Critical issues in treatment outcomes may be related to stem cells formulation and administration route. We develop a hydrogel as a cell carrier, consisting of compounds (phospholipids and hyaluronic acid-HA) naturally present in the central nervous system (CNS). The HA-based hydrogel physically crosslinked with liposomes is designed for direct injection into the CNS to significantly increase the bone marrow mesenchymal stem cells (BMSCs) bioavailability. MATERIALS AND METHODS: Hydrogel compatibility is confirmed in vitro with BMSCs and in vivo through its intracerebroventricular injection in rats. To assess its efficacy, the main cause of chronic neurologic disability in young adults is selected, namely multiple sclerosis (MS). The efficacy of the developed formulation containing a lower number of cells than previously reported is demonstrated using an experimental autoimmune encephalomyelitis (EAE) rat model. KEY FINDINGS: The distribution of the engineered hydrogel into corpus callosum can be ideal for NDs treatment, since damage of this white matter structure is responsible for important neuronal deficits. Moreover, the BMSCs-laden hydrogel significantly decreases disease severity and maximum clinical score and eliminated the relapse. SIGNIFICANCE: The engineering of advanced therapies using this natural carrier can result in efficacious treatments for MS and related debilitating conditions.

Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach.

The development of drug delivery strategies for efficacious therapeutic administration directly into the central nervous system (CNS) in a minimally invasive manner remains a major obstacle hindering the clinical translation of biological disease-modifying therapeutics. A novel direct trans-nasal delivery method, termed 'Minimally-Invasive Nasal Depot' (MIND), has proved to be successful in providing high CNS uptake and brain distribution of blood-brain barrier (BBB) impermeant therapeutics via direct administration to the olfactory submucosal space in a rodent model. The present study describes the engineering of custom-made implants with a unique architecture of an "osmotically-active core" entrapping the therapeutic and a "biodegradable polymeric shell" to enable long-acting delivery using the MIND procedure. The MIND-administered implant provided sustained CNS delivery of brain derived neurotrophic factor (BDNF) AntagoNATs for up to 4 weeks in Sprague Dawley rats resulting in significant endogenous BDNF protein upregulation in several brain tissues. The biocompatibility of such core-shell implants coupled with their substantial pharmacokinetic advantages and safety of the MIND procedure highlights the practical utility and translational potential of this synergistic approach for treatment of chronic age-related neurodegenerative diseases.

Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases.

Introduction: Neurodegenerative diseases are those wherein the neurons in the brain or peripheral nervous system lose their function, eventually culminating in neuronal death. Aging acts as the predominant factor here due to the reduced protein turnover rate in aging cells. As neurotrophic factors possess imperative roles in protecting the neurons and restoring their functionality, design of different modalities to deliver them to the brain would significantly enhance the therapeutic benefits.Areas covered: This review covers the various mechanisms of neurodegeneration, its molecular link with aging, different neurotrophic factor classes and their potentials, current treatment strategies, the challenges associated with the delivery of neurotrophic factors, administration routes, design of different delivery vehicle design, alternative modalities of delivery, and the clinical translational challenges of these strategies.Expert opinion: A deeper molecular level understanding about the complexity of neurodegeneration, discovery of potential biomarkers, which helps identifying the right targets, finding the accurate animal model completely recapitulating the human scenario, and a validated design of clinical trials would immensely help in overcoming the present challenges. The substantial developments in the field of gene therapy, usage of small molecules and peptide mimetics, combinatory approaches, etc. definitely give brighter hopes.