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Human African trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. It is caused by protozoans of the genus Trypanosoma, transmitted to humans by bites of tsetse flies (glossina) which have acquired the parasites from infected humans or animals.

American trypanosomiasis, or Chagas disease, occurs mainly in Latin America. It is caused by a different Trypanosoma subgenus, transmitted by another vector and the disease characteristics are very different from HAT.

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Later the parasites cross the blood-brain barrier into the central nervous system causing the meningo-encephalitic or second stage. Generally this is when more obvious signs and symptoms of HAT appear: behaviour changes, confusion, sensory disturbances and poor coordination. Sleep cycle disturbance, which gives the disease its name, is a prominent feature. Without treatment, HAT is usually fatal although rare cases of self-cure have been reported.

The WHO Network for HAT Elimination coordinates efforts from all stakeholders including national HAT programmes, international and non-governmental organizations, academia and donors. Network subgroups deal with the diagnostic, therapeutic, antivectorial, sociocultural, programatic and scientific aspects of HAT.

Lyme disease is the most common vector-borne disease in the United States. Lyme disease is caused by the bacterium Borrelia burgdorferi and rarely, Borrelia mayonii. It is transmitted to humans through the bite of infected blacklegged ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system. Lyme disease is diagnosed based on symptoms, physical findings (e.g., rash), and the possibility of exposure to infected ticks. Laboratory testing is helpful if used correctly and performed with validated methods. Most cases of Lyme disease can be treated successfully with a few weeks of antibiotics. Steps to prevent Lyme disease include using insect repellent, removing ticks promptly, applying pesticides, and reducing tick habitat. The ticks that transmit Lyme disease can occasionally transmit other tickborne diseases as well.

Spark Therapeutics is working to address a range of debilitating genetic diseases. Each of our investigational programs currently uses an adeno-associated viral (AAV) vector developed and manufactured by the Spark team, and in some cases, together with collaborators.

Fidanacogene elaparvovec, previously SPK-9001, is an investigational bio-engineered AAV vector utilizing a high-activity F9 transgene for hemophilia B, or factor IX deficiency. Hemophilia B is a serious and rare inherited hematologic disorder, characterized by mutations in the F9 gene, which lead to deficient blood coagulation and an increased risk of bleeding or hemorrhaging.

Viruses have evolved to be highly effective vehicles for delivering genes into cells. Seeking to take advantage of these traits, scientists can reprogram viruses to function as vectors, capable of carrying their genetic cargo of choice into the nuclei of cells in the body. Such vectors have become critical tools for delivering genes to treat disease or to label neurons and their connective fibers with fluorescent colors to map out their locations. Because viral vectors have been stripped of their own genes and, thereby, of their ability to replicate, they are no longer infectious. Therefore, achieving widespread gene delivery with the vectors is challenging. This is especially true for gene delivery to hard to reach organs like the brain, where viral vectors have to make their way past the so-called blood-brain barrier, or to the peripheral nervous system, where neurons are dispersed across the body.

Now, to enable widespread gene delivery throughout the central and peripheral nervous systems, Caltech researchers have developed two new variants of a vector based on an adeno-associated virus (AAV): one that can efficiently ferry genetic cargo past the blood-brain barrier; and another that is efficiently picked up by peripheral neurons residing outside the brain and spinal cord, such as those that sense pain and regulate heart rate, respiration, and digestion. Both vectors are able to reach their targets following a simple injection into the bloodstream. The vectors are customizable and could potentially be used as part of a gene therapy to treat neurodegenerative disorders that affect the entire central nervous system, such as Huntington's disease, or to help map or modulate neuronal circuits and understand how they change during disease.

"We have now developed a new collection of viruses and tools to study the central and peripheral nervous systems," says Gradinaru. "We are now able to get highly efficient brain-wide delivery with just a low-dose systemic injection, access neurons in difficult-to-reach regions, and precisely label cells with multiple fluorescent colors to study their shapes and connections."

"Neurons outside of the central nervous system have many functions, from relaying sensory information to controlling organ function, but some of these peripheral neural circuits are not yet well understood," says Ben Deverman, senior research scientist and director of the Beckman Institute's CLOVER Center. "The AAV-PHP.S vector that we developed could help researchers study the activity and function of specific types of neurons within peripheral circuits using genetically-encoded sensors and tools to modulate neuronal firing with light or designer drugs, respectively."

The paper is titled "Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems." In addition to Chan, Deverman, and Gradinaru, other coauthors are postdoctoral scholars Min Jang, Alon Greenbaum, Luis Snchez-Guardado, and Wei-Li Wu; graduate student Bryan Yoo; undergraduate student Namita Ravi; Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology and a Heritage Medical Research Institute Investigator; and research professor Carlos Lois. Funding was provided by the National Institutes of Health, the Presidential Early Career Award for Scientists and Engineers, the Heritage Medical Research Institute, the Beckman Institute and Rosen Center at Caltech, the Gordon and Betty Moore Foundation, the Shurl & Kay Curci Foundation, the Hereditary Disease Foundation, the Friedreich's Ataxia Research Alliance (FARA) and FARA Australasia, and the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office.

A newly developed viral vector, AAV-PHP.S, was used to label neurons lining the digestive tract with a cocktail of three distinct fluorescent proteins. Due to the stochastic uptake of viruses encoding either a blue, green, or red fluorescent protein, cells are labeled with a wide range of hues. This multicolor approach can be used to differentiate neighboring neurons for morphology and tracing studies. [Chan et al., Gradinaru Lab; Nature Neuroscience]

The new vectors could help researchers study the activity and function of specific types of neurons within peripheral circuits using genetically encoded sensors and tools to modulate neuronal firing with light or designer drugs, respectively. The new vectors could also deliver genes that code for colorful fluorescent proteins, proteins that are useful in identifying and labeling cells.

This review focuses on adeno-associated virus (AAV) gene therapies for diseases of the central nervous system. An overview of advances in AAV vector design for therapy is provided, along with a description of current strategies to develop AAV vectors with tailored tropism. Next, progress towards treatment of neurodegenerative diseases is presented at both the pre-clinical and clinical stages, focusing on a few select diseases to highlight broad categories of therapeutic parameters. Special considerations for more challenging cases are then discussed in addition to the immunological aspects of gene therapy.

The need for long-lasting and transformative therapies for neurodevelopmental disorders cannot be understated. Traditional drug development is made particularly difficult for these disorders due to the blood-brain-barrier (BBB) and off-target effects of drugs affecting neuronal function. Central nervous system (CNS)-directed gene therapy via gene replacement represents a powerful modality to achieve long-term correction of disorders following a single treatment. Multiple vectors exist that can be used for gene therapy, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors [1]. While lentiviral vectors offer stable transduction and roughly double the packaging capacity of AAV, in the context of CNS-directed gene therapy, lentiviral vectors have been more amenable to ex vivo treatment approaches and thus far not as amenable as AAV for in vivo gene transfer to widely target the CNS [2, 3]. Even though other viral vectors have shown promise in certain CNS gene therapy applications, this review will focus specifically on the progression towards and beyond the current generation of CNS-directed AAV gene therapeutic strategies. Information on basic AAV biology and vector properties is reviewed elsewhere [1, 2]. Pre-clinical and clinical progress towards the treatment of various neurodevelopmental disorders will be covered to highlight the various challenges and potential therapeutic modalities encountered with AAV gene therapy. Finally, some special considerations for AAV-mediated gene therapy, including potential immune responses, will be discussed. ff782bc1db