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Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

Introduction Lipid based nanoparticles (LNPs) are clinically successful vectors for hepatic delivery of nucleic acids. These systems are being developed for non-hepatic delivery of mRNA for the treatment of diseases like cystic fibrosis or retinal degeneration as well as infectious diseases. Localized delivery to the lungs requires aerosolization. We hypothesized that structural lipids within LNPs would provide features of integrity which can be tuned for attributes required for efficient hepatic and non-hepatic gene delivery. Herein, we explored whether naturally occurring lipids that originate from the cell membrane of plants and microorganisms enhance mRNA-based gene transfection in vitro and in vivo and whether they assist in maintaining mRNA activity after nebulization. Methods We substituted DSPC, a structural lipid used in a conventional LNP formulation, to a series of naturally occurring membrane lipids. We measured the effect of these membrane lipids on size, encapsulation efficiency and their impact on transfection efficiency. We further characterized LNPs after nebulization and measured whether they retained their transfection efficiency. Results One plant-derived structural lipid, DGTS, led to a significant improvement in liver transfection of mRNA. DGTS LNPs had similar transfection ability when administered in the nasal cavity to conventional LNPs. In contrast, we found that DGTS LNPs had reduced transfection efficiency in cells pre-and post-nebulization while maintaining size and encapsulation similar to DSPC LNPs. Conclusions We found that structural lipids provide differential mRNA-based activities in vitro and in vivo which also depend on the mode of administration. Understanding influence of structural lipids on nanoparticle morphology and structure can lead to engineering potent materials for mRNA-based gene therapy applications.

Antibody immunotherapy is revolutionizing modern medicine. The field has advanced dramatically over the past 40 years, driven in part by major advances in isolation and manufacturing technologies that have brought these important biologics to the forefront of modern medicine. However, the global uptake of monoclonal antibody (mAb) biologics is impeded by biophysical and biochemical liabilities, production limitations, the need for cold-chain storage and transport, as well as high costs of manufacturing and distribution. Some of these hurdles may be overcome through transient in vivo gene delivery platforms, such as non-viral synthetic plasmid DNA and messenger RNA vectors that are engineered to encode optimized mAb genes. These approaches turn the body into a biological factory for antibody production, eliminating many of the steps involved in bioprocesses and providing several other significant advantages, and differ from traditional gene therapy (permanent delivery) approaches. In this review, we focus on nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others.

Understanding the mechanisms that underlie age-related macular degeneration (AMD) has led to the identification of key molecules. Hypoxia-inducible transcription factors (HIFs) have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of nAMD. This knowledge has propelled the development of a new group of therapeutic strategies focused on gene therapy. The present review provides an update on current gene therapies in ocular angiogenesis, particularly nAMD, from both basic and clinical perspectives.

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.

Exosomes are nano-sized vesicles involved in intercellular communication via delivery of molecules including lipids, nucleic acids, proteins, or other cellular components to distant or neighboring sites. Their ability to pass biological barriers, stability in physiological fluids without degradation, and distinctive affinity to target cells make exosomes very remarkable therapeutic vehicles. Virus-based approaches are some of the most widely used gene therapy methods; however, there are many issues need to be clarified such as high immunogenicity. Using of the exosomes procures the functional transfer of their cargo with minimal intervention from the immune system and it has been reported to be secure and well-tolerated. When the regenerative medicine is taken into consideration, stem cell-based approaches have been aimed to utilize but the general efficacy and safety profile of stem cell therapy has still not been enlightened. At this point, stem cell-derived exosomes exhibit a way to procure cell-free regenerative medicine with their unique characteristics. Exosomes are considered as appropriate and highly stable biological nano-vectors taking part in a wide variety of healthy and pathological processes for advanced targeted therapies. However, there are still crucial obstacles to achieve efficient isolation of large amount of specific and pure exosomes. Thus, large-scale exosome production under good manufacturing practice is required. The purpose of this review is to focus on stem cell-based exosomes for gene delivery and to introduce synthetic exosome-mimics as a potential alternative in the field of targeted gene therapies. Further, we aim to highlight the biobanking and large-scale manufacturing methods of exosomes.

The treatment of cellular primary immunodeficiencies has benefitted from significant advances in the field of allogeneic stem cell transplantation (alloHSCT). However, while this therapy is curative for many PIDs, the procedure requires a suitably matched donor and carries significant risks of morbidity and mortality from complications such as graft-versus-host disease (GVHD). Autologous gene therapy (GT) approaches using stem cells isolated from patients and modified ex vivo using viral vectors or gene editing techniques have the potential to offer curative therapy for PID without the immunological complications of alloHSCT. GT for PID has been developed over the last 30 years, and while several setbacks have been encountered along the way, there is now a licensed GT product for ADA-SCID, and promising results from phase I/II clinical trials have demonstrated that GT may offer clinical efficacy comparable to alloHSCT in several other PIDs. Developments in the field are broadening the application of GT, and we expect that this therapeutic modality may become standard of care for the management of several PIDs in the near future. This chapter explores the development of GT over the last 30 years and outlines its role in the management of cellular primary immunodeficiencies.

In December 2017, Luxturna® became the first FDA-approved gene therapy for any genetic disease – targeting inherited retinal dystrophies caused by biallelic mutations in the RPE65 gene – and the first accepted application of a therapeutic adeno-associated virus (AAV) in the United States. In fact, half of the novel ophthalmic drug approvals over the past 4 years (2017–2020) have been in rare and orphan eye diseases. This includes groundbreaking work in gene therapies, biologics, and traditional medicine.

In order to correct the genetic defects that are fundamental reasons for many pathologies, gene therapy uses exogenous nucleic acids for intentional modulation of gene expression in specific cells. Due to the large size and the negative charge of exogenous nucleic acids, the delivery of these macromolecules is typically mediated by carriers or vectors. Viral carriers are known to be very efficient however, they have a severe drawbacks such as toxicity and immunogenicity. In this regard, gene-based therapy using non-viral approaches has drawn increasing attention, and has become an important field of research. The diversity of materials used as of non-viral vectors known today highlights the recent progress of gene-based therapy using non-viral approaches. Herein, we describe the progress made by our group in the development of hybrid vectors that combine key features of classical carriers design rationally or formed by combinatorial approach using dynamic chemistry which are remarkable strategies to address the current challenges in gene delivery.

Severe combined immunodeficiencies (SCID) are a heterogeneous group of rare, genetic diseases resulting in profoundly impaired adaptive immune responses. SCID is fatal without treatment due to the development of severe, recurrent infections. The establishment of universal newborn screening (NBS) for SCID and optimization of hematopoietic stem cell transplantation (HSCT), the curative treatment for SCID, have led to improved detection and early treatment of patients with SCID, which has significantly reduced morbidity and mortality. Despite these diagnostic and therapeutic tools, significant challenges remain such as normalizing thresholds for newborn screening, preventing peri-transplant infection, choosing conditioning regimens that balance toxicity with immunosuppression, post-transplant monitoring, and addressing the quality-of-life and social needs of SCID patients and their families. Advances in molecular biology have led to the development of novel genetic therapies for particular subtypes of SCID, notably adenosine deaminase (ADA) deficiency, which provide promising ways to address many of these challenges. Future guidelines will need to incorporate a mutation-specific approach to optimize HSCT parameters and gene therapy recommendations so personalized medical care to SCID patients can be provided.

Sickle cell disease (SCD) is an inherited red blood cell disorder with significant morbidity and decreased survival in affected patients. Hematopoietic cell transplantation (HCT) has been shown to be curative in both children and adults. However, utilization has been limited due to toxicity, donor availability, and a high incidence of graft rejection. Emerging therapeutic options including alternative donor transplantation and gene therapy are providing new opportunities for SCD patients; however, many of these therapies are still under investigation.

Gene therapy has been proven to be a promising tool to treat chronic and acquired diseases because it allows us to regulate a gene sequence by repairing, replacing, or silencing a target gene. In this chapter, gene therapy involving gene silencing by RNA interference (RNAi) will be presented and discussed, as well as its advantages and disadvantages. Furthermore, it will also present nanocarriers for the topical and systemic administration of small interfering RNA (siRNA, the RNA effector molecule) and the advantages and disadvantages of each system will be addressed. Recent clinical and preclinical advances involving delivery systems for siRNA application will be emphasized. The chapter will end by addressing the future perspectives of the specific knockdown of therapeutic targets by RNA interference.

Cellular and gene therapies have long been associated with and focused on rare diseases, and these potentially curative therapies (gene therapy in particular) are relatively rare among therapeutic options. Diseases that can be addressed by modifying a singular gene (monogenic) are easier to target than diseases affected by multiple gene interactions, and a particularly high number of rare diseases are monogenic. These types of therapies can possibly enable patients to live functional lives, free caregivers to do the same, lessen the economic burden of care, and decrease the strain on healthcare systems. Five of the seven approved gene therapies available in the US or EU market as of July 2020 target rare diseases. With hundreds more in development, the ties between cell and gene therapies and rare diseases will only increase over time.

Lysosomal storage disorders (LSDs) are rare inborn errors of metabolism caused by defects in lysosomal function. These diseases are characterized by accumulation of completely or partially degraded substrates in the lysosomes leading to cellular dysfunction of the affected cells. Currently, enzyme replacement therapies (ERTs), treatments directed at substrate reduction (SRT), and hematopoietic stem cell (HSC) transplantation are the only treatment options for LSDs, and the effects of these treatments depend strongly on the type of LSD and the time of initiation of treatment. However, some of the LSDs still lack a durable and curative treatment. Therefore, a variety of novel treatments for LSD patients has been developed in the past few years. However, despite significant progress, the efficacy of some of these treatments remains limited because these therapies are often initiated after irreversible organ damage has occurred.

Most of the newly approved medicines are based on biotechnology. These include biological therapy, which is defined as a type of treatment that uses substances made from living organisms to treat disease. This chapter described the neurological complications of cell therapy, gene therapy, and vaccines. CAR-T cells can have neurotoxic effects and induce a cytokine release syndrome. Stem cell transplantation the brain may lead to tumor formation. Gene therapy can also have neurotoxicity. Adeno-associated viral vector-mediated gene therapy may induce inflammation in the brain. Neurologic adverse effects of vaccines used for infections affecting the nervous system are sometimes difficult to distinguish from the manifestations of the disease. The most significant neurologic complication of vaccination is acute disseminated encephalomyelitis, a syndrome characterized by rapid development of multifocal neurologic dysfunction.

This chapter provides an analysis of global trends in genomic vaccines, a radical innovation breakthrough (RIB), from technological foresight and pandemic preparedness perspectives, crucial in times of COVID-19. From this conceptual framework, the state-of-the-art and technological prospects for these genomic vaccines are examined, based on a search on scientific publications and on patents for the period 2010–2020, presenting the vaccine patent landscape for the period. This search provides an overview of recent breakthroughs in genomic vaccines and two other related RIBs, gene editing and gene therapy, and identifies novel strategies that could positively contribute to the development of future genomic vaccines to pandemic diseases and COVID-19. Our results evidence in the last decade extraordinary advances in genetic approaches, gene editing and gene therapy, and the rapid development of innovative DNA/RNA vaccines for the prevention and immunotherapy of an extensive diversity of diseases, from the neglected infectious ones to cancer therapy. These results highlight the flexibility of vaccine technological platforms, crucial for response to pandemics and COVID-19, including hepatitis B, varicella, chronic obstructive pulmonary disease, autoimmune diseases – systemic lupus erythematosus, lupus nephritis, and autoimmune myasthenia gravis – and finally a new nucleic acid sequence for immunogenicity to SARS-CoV-2.

Clinical investigation of gene- and stem cell-based therapies has greatly expanded in recent years with treatment aimed at a diverse array of inherited retinal disorders (IRDs) (Garafalo et al. Prog Retin Eye Res, 2019:100827; Takahashi et al. Ophthalmic Genet, 2018;39:560–568) and non-hereditary retinal degenerations. Access to the subretinal and/or suprachoroidal space (SCS) is of particular interest for targeted delivery of retinal genetic or cellular therapeutics. Surgical approaches for suprachoroidal and suprachoroidal-to-subretinal gene and cell therapy delivery continue to be refined as new treatment modalities are developed. The safety, efficacy and durability of emerging therapies will also need to be validated in the context of their delivery method. This chapter will explore the potential advantages of therapeutic delivery via the SCS and compare with other approaches. More research is warranted to improve technique-related safety, ease of use, and reproducibility of the current methodologies.

Age-related neurodegenerative diseases have detrimental consequences on health of many patients and result in mortality. The current treatment options are limited and usually fail to correct the underlying pathology. AAV-based gene therapies have proved to be safe based on the data available on clinical trials for several monogenic diseases. Therefore, such therapies can pave the way to treat neurodegenerative diseases likes Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Here, the advantages of AAV-based gene therapies are discussed with emphasis on efforts of developing novel capsids with superior therapeutic efficacy. Furthermore, the results of clinical trials on AD, PD, and ALS are summarized.

During the last three decades, there has been significant progress in our understanding of the cellular and molecular basis of normal functions in cardiomyocytes as well as the alterations in the homeostatic mechanisms that lead to pathological states in these cells. Thanks to these advances in our knowledge, there has been great gains in attempts to identify disease biomarkers and therapeutic targets for several heart diseases. Biomarkers are indicators of structural and functional changes in pathological conditions. They are useful to detect disease associated changes in tissues or body fluids. Thus, they are important tools for disease diagnosis, assessing severity of the disease, identifying possible treatment strategies and predicting prognosis. Several biochemical, molecular and genetic biomarkers of heart diseases are in clinical use or under evaluation. Novel therapeutic targets and strategies which enhance clinical efficacy in patients with heart diseases are also currently available. The treatment approaches under trial for ischemic heart disease and heart failure include the use of molecules such as micro RNAs, transcription factors and growth factors, cell therapy, gene therapy, epigenetic therapy, modulation of cardiomyocyte death, metabolic therapies and senolytics. CRISPR-Cas9-based gene editing technology is gaining much attention for its potential therapeutic use in congenital heart defects.

Advances in nanotechnology, chemistry and molecular biology are making possible the transformation of conventional medicine into a personalized one where we are increasingly talking about intelligent drug carriers and targeted delivery of drugs and genes. Gene therapy emerges as a new field in biomedical research and seeks to establish a roadmap to the clinic and the market by promising solutions to incurable diseases. Various approaches are being tried for the implementation of gene therapy, on the one hand viral transporters and on the other hand non-viral solutions. Along with non-viral transfection vector design and synthesis, in vitro biological evaluation is required to investigate both the ability of vectors to transfect, and their good biocompatibility. For accurate and reliable outcomes, the choice of the correct method is essential.

Spinocerebellar ataxia type 1 (SCA1) is one of the intractable neurodegenerative diseases caused by the mutation of Ataxin-1 (Atxn1) gene. By various comprehensive approaches, we have newly discovered key molecules such as PQBP1, VCP, HMGB1, RpA1, and YAP/YAPdeltaC that mediate the SCA1 pathology from the gene mutation to phenotypes. The functions of these molecules are involved in transcription, RNA splicing, and DNA damage repair, and their functional impairments contribute to neurodegeneration via multiple pathways. Based on the knowledge, we have also developed gene therapies using adeno-associated virus and other disease-modifying therapies. In this review, we focus on summarizing our original works for understanding and conquering SCA1.

Gene therapy has the potential to introduce a new approach to treating Sjogren’s syndrome. In the last 10 years, gene therapy has advanced from preclinical to approved drugs for a diverse set of conditions, including blindness, neurologic disease, and hemophilia. Many aspects of Sjogren’s syndrome are suited to current vectors and promoters. Preclinical studies in animal models of Sjogren’s syndrome have yielded promising results. In this chapter, we will review the current state of gene transfer technology, its applications, different aspects of vector systems applicable in Sjogren’s syndrome, relevant animal models for preclinical studies, and their outcomes as well as future directions for advancement.

Phagocytes form the first line of defense against invading pathogens and play a key role in wound healing following tissue injury. A broad range of monogenic defects affecting phagocyte numbers and/or function have been described. A common hallmark of all congenital defects of phagocytes is an increased susceptibility to severe bacterial and fungal infections. Typical sites of infection are the skin, the oral mucosa and gingiva, lymph nodes, the lungs, and other internal organs. Furthermore, many congenital phagocyte disorders are associated with an increased risk of inflammatory manifestations and/or hematological malignancies. In the 1950s, survival of the first described disorders was dramatically poor with most patients dying from infectious complications in the first years of life. However, in the past decades, advances in diagnosis and treatment strategies have significantly improved patient outcome. In addition, the increased understanding of the molecular disease mechanisms has paved the way for gene therapy as a promising new treatment option. This chapter outlines the current knowledge on congenital defects of phagocytes, categorized according to their major underlying defect.

Appropriate gene carriers are vital components of gene therapy for treating numerous intractable diseases. Compared with viral carriers, non-viral carriers exhibit lower immunogenicity and higher biosafety, which have received increasing attention. In particular, among non-viral vectors, gene vectors based on chitosan derivatives are considered a promising gene therapy tool and have been extensively studied due to the biocompatibility, biodegradability, and modifiability of chitosan. In this review, we first discussed the influence of chitosan parameters on the efficiency of gene therapy. More importantly, we summarized the recent research progress in various diseases of chitosan derivatives to deliver different gene therapy substances including plasmid (pDNA), short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), and clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPER-Cas9) system. Finally, the current challenges and future directions of chitosan derivatives as gene carriers are also proposed.

Stem cells play a pivotal role in the developmental stages of an organism and in adulthood as well. Therefore, it is not surprising that stem cells constitute a focus of extensive research. Indeed, several decades of stem cell research have tremendously increased our knowledge on the mechanistic understandings of stem cell biology. Interestingly, revealing the fundamental principles of stem cell biology has also fostered its application for therapeutic purposes. Many of the attributes that the stem cells possess, some of which are unique, allow multifaceted exploitation of stem cells in the treatment of various diseases. Cancer, the leading cause of mortality worldwide, is one of the disease groups that has been benefited by the potentials of therapeutic applications of the stem cells. While the modi operandi of how stem cells contribute to cancer treatment are many-sided, two major principles can be conceived. One mode involves harnessing the regenerative power of the stem cells to promote the generation of blood-forming cells in cancer patients after cytotoxic regimens. A totally different kind of utility of stem cells has been exercised in another mode where the stem cells can potentially deliver a plethora of anti-cancer therapeutics in a tumor-specific manner. While both these approaches can improve the treatment of cancer patients, there exist several issues that warrant further research. This review summarizes the basic principles of the utility of the stem cells in cancer treatment along with the current trends and pinpoints the major obstacles to focus on in the future for further improvement.

Radiation therapy can be modified by increasing the effectiveness of radiation on tumors (radiosensitizers), protecting normal tissues (radioprotectors), increasing oxygen concentration, or by using systemic therapy drugs. Radioprotectors are described by their dose reduction factor (DRF) while radiosensitizers are described by their enhancement ratio (ER). Both numbers are a ratio of radiation doses required to achieve a biological effect. Systemic agents can be classified as hypoxic radiosensitizers, hypoxic cytotoxins, classic alkylators, platinum agents, antibiotics, antimetabolites, vinca alkaloids, taxanes, topoisomerase inhibitors, hormonal agents, monoclonal antibodies, small molecule inhibitors (usually tyrosine kinase inhibitors), and immunomodulators. Progress is also being made in the field of gene therapy, although this is not yet mainstream.

Treatment of CNS disorders is limited by difficulties in drug delivery to the site of action, and several methods have been used to deliver drugs directly to the brain. Important strategies include facilitation of passage of systemically administered drugs across the blood-brain barrier. Some of the drug-induced neurological disorders are either due to the method of delivery, malfunction of a delvery device, or inappropriate amount of drug delivered.

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In gliomas different strategies have use: (1) release of suicide genes to produce cytotoxic compounds in the tumor and provoke tumor cell death, (2) oncolytic virotherapy, (3) release of tumor-suppressor genes, (4) immunomodulatory gene therapy, that stimulates an antitumoral immune response, and (5) the use of synthetic vector particles/nanoparticles to deliver genetic material thereby silencing genes essential to tumorigenesis. Several clinical trails have use gene therapy alone or with other therapies in gliomas, but at the time there is not any gene therapy approve for treatment or prevention in gliomas.

Lower extremity arterial disease affects more than 200 × 10e6 people worldwide causing Critical Limb Ischemia (CLI), also referred to as chronic limb-threatening ischemia (CLTI) a life-threatening disease and the major cause of ischemic amputation. For nonrevascularizable patients, the outlook is bleak and novel therapies are needed. This chapter discusses new approaches including gene therapy and stem/progenitor cell (SPC)-based therapies, including autologous bone marrow-derived cells (BM), MB-mononuclear cells (BM-MNC), mesenchymal stem cells (MSC), mobilized bone marrow cell (PB-MNC), allogeneic cells and ex vivo expanded or activated/differentiated cell products. A preliminary first-in-human trial of a novel treatment is presented that combines immune cell therapy and a stepwise activation and differentiation of SPC. Cells from a standard blood draw (with no pretreatment or mobilization) are transformed, within a day, into a therapeutic product (BGC101) composed of endothelial progenitor cells (EPCs), SPCs, dendritic cells (DCs), and T helper cells. BGC101 was found safe and effective in stabilizing and reversing the course of CLI. Controlled studies on a larger population are planned to evaluate this new concept.

Peripheral arterial disease (PAD) is a major complication of systemic atherosclerosis and is a major public health threat worldwide. For patients with PAD, there are limited options for therapy, and no medications have been shown to slow progression of the disease. For patients with severe disease, open surgical procedures and endovascular techniques may relieve symptoms and prevent amputation; however, in a substantial proportion of patients, surgical and endovascular revascularization are not an option based on a patients’ anatomy and/or comorbid diseases. “Stem cell therapy” covers a range of investigational approaches across various cells and delivery methods. Overall, stem cell therapy has been shown to be safe, and multiple small studies have shown benefit in pain relief, improved functional status, and decreased major amputations. Unfortunately, the results of larger trials of stem cell therapy have been largely disappointing, and many of the early studies may well have been limited by both selection bias and lack of investigator blinding. In this chapter, the embryological basis for therapy with stem cells will be reviewed, as well as major studies that set the stage for stem cell therapy as an option or those that provide important findings. The current status of stem cell therapy and future directions for this area of research will also be discussed.

Parkinson’s disease (PD) is a neurodegenerative disorder that carries large health and socioeconomic burdens. Current therapies for PD are ultimately inadequate, both in terms of symptom control and in modification of disease progression. Deep brain stimulation and infusion therapies are the current mainstay for treatment of motor complications of advanced disease, but these have very significant drawbacks and offer no element of disease modification. In fact, there are currently no agents that are established to modify the course of the disease in clinical use for PD. Gene and cell therapies for PD are now being trialled in the clinic. These treatments are diverse and may have a range of niches in the management of PD. They hold great promise for improved treatment of symptoms as well as possibly slowing progression of the disease in the right patient group. Here, we review the current state of the art for these therapies and look to future strategies in this fast-moving field. Electronic supplementary material The online version of this article (10.1007/s13311-020-00940-4) contains supplementary material, which is available to authorized users.

Since genetic disruptions provoke a noticeable proportion of cancers, correcting genes’ deficit accounts for promising approaches for cancer treatment. Advances in designing tumor-selective viral and nonviral vectors allow for more efficient gene delivery. Clinically approved gene therapies can be classified into several approaches such as sensitizing tumors to chemotherapies, targeting angiogenesis, and restoring tumor suppressing functions. Adjacent cells in tumors can enhance the transfection efficacy through the “bystander effect” in which delivered genes and toxic metabolites are transported between cells through gap junctions.

The biomedical applications of mesenchymal stem cells (MSCs) have gained expanding attention over the past three decades. MSCs are easily obtained from various tissue types (e.g. bone marrow, fat, cord blood, etc.), are capable of self-renewal, and could be induced to differentiate into several cell lineages for countless biomedical applications. In addition, when transplanted, MSCs are not detected by immune surveillance, thus do not lead to graft rejection. Moreover, they can home towards affected tissues and induce their therapeutic effect in a cell-base and/or a cell-free manner. These properties, and many others, have made MSCs appealing therapeutic cell candidates (for cell and/or gene therapy) in myriad clinical conditions. However, similar to any other therapeutic tool, MSCs still have their own limitations and grey areas that entail more research for better understanding and optimization. Herein, we present a brief overview of various pre-clinical/clinical applications of MSCs in regenerative medicine and discuss limitations and future challenges.

Cystic fibrosis (CF) is the most common fatal genetic disease in the US. Since the sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, better characterization of CFTR mutations led CF to become the first lung disease applying personalized medicine for diagnostic and therapeutic purposes. Advances in CFTR modulators, gene therapy, and new drug efficacy screening methods are creating individualized treatment opportunities the majority of CF patients regardless of their CFTR genotype. These investigative efforts will define novel and personalized therapeutic targets that minimize the impact of CF on the health and quality of life of our patients.

As it was already mentioned in the first chapter of this book, but will also be made clear throughout the remaining chapters, the term gene therapy encapsulates different approaches and applications based on the use and delivery of different nucleic acids. The most straightforward and perhaps most simple strategy for a gene-based therapy consists in adding a new protein-coding gene, which is an approach called gene augmentation therapy (Fig. 6.1). For monogenic recessive disorders in which the causative mutated is nonfunctional, the therapeutic gene to be delivered will be the normal wild-type form of the gene. The delivery of a correct copy of the gene is expected to restore the production of the defective or missing protein and thus revert the disease phenotype. This type of gene augmentation therapy is often also referred to as gene replacement therapy. As already discussed, this rationale was behind the first gene therapy clinical trial performed and is also at the basis of the majority of the gene therapy clinical trials performed so far.

Nucleic acids have gained significant interest in medicine for their therapeutic and prophylactic application. However, if delivered alone, nucleic acids are susceptible to nuclease degradation. Hence, delivering them with a suitable delivery system which can protect them could be beneficial. There is an increasing demand for novel delivery systems for nucleic acids to use them as vaccines and for gene therapy. Out of many types of delivery systems, nanoparticles are gaining importance because of their suitable properties. Hence, this chapter mainly focuses on discussing various types of nanoparticles for the delivery of nucleic acids. Recent applications of various types of nanoparticle-based viral and non-viral vectors and their advantages and disadvantages will be discussed in detail. The potential improvements which can be made to each existing nanoparticle systems are expressed. Overall this chapter is to provide an overview of importance of nanoparticles for nucleic acid delivery and is targeted towards beginners as well as advanced researchers in the field.