Written by Dr. Marija Cvetanovic Edited by Dr. Ronald Buijsen
Researchers from the University of California show they can “edit” the Frataxin gene in human cells from Friedreich’s Ataxia and transplant them into mice. This lays the groundwork for this method to be tested for safety.
Friedreich’s ataxia is a progressive, neurodegenerative movement disorder. It is often associated with heart issues and diabetes. Symptoms first start to appear in patients when they are around 10 to 15 years old. Friedreich’s ataxia has the prevalence of approximately 1 in 40,000 people and is inherited in a recessive manner. This means that patients with Friedreich’s ataxia inherited a disease gene from both the father and mother. Friedreich’s ataxia is caused by an overexpansion of the GAA repeat in the Frataxin gene, all these extra repeats causes less Frataxin protein to be made.
Human hematopoietic stem and progenitor cells (HSPCs) are the stem cells that give make to other types of blood cells. You can find HSPCs in the blood all around the body.
HSPCs are ideal candidates for use in stem cell therapy because of a few reasons. First, you can easily get them out of the body through a blood donation (at least easier than some other types of cells!). Second, they can self-renew, meaning they will make more of themselves. Third, other folks have researched this type of cell before, so we know they are fairly safe. Researchers wanted to test if these cells could be used to help treat Friedreich’s ataxia.
A new therapeutic compound shows promise to treat Friedrich’s ataxia.
What is Friedrich’s ataxia (FA)?
Friedrich’s ataxia is a genetic neurodegenerative disease that affects many organs, most notably nerves, muscles, and heart. FA is a recessive ataxia. Symptoms typically present in childhood and result in significant physical disability. Cognition (thinking, memory) remains intact.
Some of the symptoms a person with FA may experience include ataxia (loss of movement coordination), fatigue, muscle weakness, cardiomyopathy (heart issues), scoliosis (curvature of the spine) and sensory impairments (vision, hearing). Life expectancy is reduced as a result of the disease.
The genetic change that is present in FA affects the production of a protein called frataxin. Frataxin deficiency leads to abnormal iron accumulation in mitochondria. As mitochondria are critical for energy metabolism and other important functions in cells, their dysfunction causes faulty energy production and undesirable toxicity in the form of reactive oxygen species.
There is currently no treatment available to patients with FA.
How does Omaveloxolone work?
Omevaloxolone is a synthetic compound. It works by counteracting deficits seen in disease at the cellular level. Omevaloxolone promotes Nrf2, which works to activate a series of defence mechanisms that help cells handle oxidative stress (mentioned above). Nrf2 is also important for improving the energy production machinery mitochondria require to function efficiently. Thus, by activating Nrf2, Omevaloxolone is thought to mitigate oxidative damage, improve energy production, and promote neuroprotection. Additionally, Omevaloxolone and similar compounds exhibit anti-inflammatory action.
What exactly has been validated?
In the MOXIeclinical trial, study participants with FA from several countries were randomized to either daily omaveloxolone (drug) or placebo (control). Their neurological function, activities of daily living, and ataxia were assessed at baseline (at the beginning) and after 48 months of receiving treatment. At the end of this period, the data showed statistically significant improvement in each of these measures. Participants who received omaveloxolone fared better than those who did not (placebo). Additionally, participants who received omaveloxolone saw improvements after treatment compared to their own baseline at the beginning of the study.
What is happening next?
The next step in testing omaveloxolone is to have a long-term study to examine its safety (and any side effects) over the course of a few years. Instead of having a control group in this type of study, called an open-label extension, now everyone enrolled received the same amount of omaveloxolone. This study is already underway and is expected to be completed by 2022. There have been some modifications to the long-term safety study in response to COVID-19, but Reata doesn’t expect there to be a significant delay in their timelines.
Se você leu o título deste artigo e não fazia ideia do que é Caenorhabditis elegans, você não está sozinho! Caenorhabditis elegans, mais comumente conhecido como C. elegans, são vermes microscópicos que normalmente crescem até 1 mm de comprimento. C. elegans são naturalmente encontrados em todo o mundo em solos onde há vegetação podre. Se você estiver se sentindo corajoso, tente localizá-los no adubo caseiro da sua casa! Embora esses vermes sejam menos familiares ao público em geral, C. elegans são bem conhecidos pelos cientistas, pois o estudo desses pequenos vermes nos ensinou muito sobre doenças humanas.
Por que C. elegans é usado como modelo?
elegans foi isolado pela primeira vez em 1900 e, desde o final da década de 1960, tem sido usado para “modelar” doenças humanas. Isso ocorre porque C. elegans e humanos compartilham algumas características fisiológicas comuns e têm uma sobreposição significativa em seus códigos genéticos. O SCAsource publicou anteriormente um Saiba Mais em modelos de camundongos, amplamente utilizados na pesquisa de ataxia. Embora C. elegans não seja amplamente utilizado na pesquisa de ataxia, há muitas vantagens em usar C. elegans como modelo:
C. elegans é de manutenção barata, permitindo a triagem de milhares de medicamentos a um custo relativamente baixo. Uma vez administrados, os cientistas podem estudar os efeitos das drogas no movimento, desenvolvimento e função do sistema nervoso de C. elegans.
C. elegans é fácil de cultivar em laboratório.
C. elegans são hermafroditas auto-fertilizantes, o que significa que eles podem se reproduzir sem um parceiro sexual. Um único hermafrodita pode produzir de 300 a 350 filhotes por um período de três dias, permitindo que os cientistas estudem facilmente um grande número de vermes que possuem as mesmas características genéticas.
Os cientistas podem manipular facilmente o genoma de C. elegans para estudar muitas doenças humanas.
Como C. elegans é transparente, seus órgãos internos, incluindo o sistema nervoso, podem ser visualizados sem dissecção.
Como C. elegans pode ser usado para estudar a neurodegeneração?
O sistema nervoso de um C. elegans é composto de algumas centenas de neurônios, o que é relativamente simples comparado ao cérebro humano (que contém cerca de 86 bilhões de neurônios). Devido a essa simplicidade, os cientistas usaram C. elegans para desenvolver modelos para várias doenças neurodegenerativas, incluindo Alzheimer, Parkinson, ataxia de Friedreich e, mais recentemente, ataxia espinocerebelar do tipo III (SCA3). O modelo SCA3 C. elegans foi desenvolvido por um grupo de pesquisa em Portugal liderado pela Dra. Patrícia Maciel, e é o primeiro do gênero no campo da ataxia espinocerebelar. Esses vermes expressam a proteína humana que causa SCA3 em todos os seus neurônios, resultando em disfunção motora de início adulto que se assemelha ao que vemos em pacientes com SCA3.
A neurodegeneração (dano / morte de neurônios) em C. elegans é monitorada marcando os neurônios com um marcador que brilha em verde sob um tipo específico de luz. A saúde dos neurônios é então avaliada, possibilitando determinar se a neurodegeneração ocorreu. A imagem acima mostra um neurônio saudável de C. elegans à esquerda, que parece intacto, comparado a um neurônio danificado de C. elegans, à direita, com uma ruptura (seta branca). Ser capaz de distinguir entre neurônios saudáveis e danificados em C. elegans é muito útil, pois os cientistas podem usar essa ferramenta para testar diferentes maneiras de reparar ou proteger os neurônios. Se os cientistas forem capazes de retardar ou impedir a neurodegeneração em C. elegans, existe o potencial de que essa descoberta possa eventualmente ajudar a tratar a neurodegeneração humana também.
Espero que este breve resumo tenha lhe mostrado que existe um enorme potencial científico nesses minúsculos vermes! Compreender a biologia de C. elegans fornece informações sobre a biologia humana, como como ocorre a neurodegeneração e o que podemos fazer para impedi-la.
If you read the title of this article and had no idea what Caenorhabditis elegans are, you are not alone! Caenorhabditis elegans, more commonly known as C. elegans, are microscopic worms that typically grow up to 1 mm in length. C. elegans are naturally found worldwide in soil where there is rotting vegetation. If you are feeling brave, you can try to locate them in your household compost! Although these worms are less familiar to the general public, C. elegans are well known to scientists, since studying these tiny worms has taught us a lot about human disease.
Why are C. elegans used as a model system?
C. elegans were first isolated in 1900 and, since the late 1960s, have been used to “model” human disease. This is because C. elegans and humans share some common physiological features and have a significant overlap in their genetic codes. SCAsource previously published a Snapshot on mouse models, which are widely used in ataxia research,. Although C. elegans are not used as widely in ataxia research, there are many advantages to using C. elegans as a model system:
C. elegans are inexpensive to maintain, allowing for the screening of thousands of drugs at a relatively low cost. Once administered, scientists can study the drugs’ effects on C. elegans movement, development, and nervous system function.
C. elegans are easy to grow in the laboratory.
C. elegans are self-fertilizing hermaphrodites, meaning that they can reproduce without a sexual partner. A single hermaphrodite can produce 300-350 offspring over a 3-day period, allowing scientists to easily study a large number of worms that have the same genetic characteristics.
Scientists can easily manipulate the genome of C. elegans to study many human diseases.
Because C. elegans are transparent, their internal organs, including the nervous system, can be imaged without dissection.
How can C. elegans be used to study neurodegeneration?
The nervous system of a C. elegans is made up of a few hundred neurons, which is relatively simple compared to the human brain (which contains about 86 billion neurons). Because of this simplicity, scientists have used C. elegans to develop models for several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Friedreich’s ataxia and, more recently, spinocerebellar ataxia type III (SCA3). The SCA3 C. elegans model was developed by a research group in Portugal led by Dr. Patrícia Maciel, and it is the first of its kind in the spinocerebellar ataxia field. These worms express the human SCA3-causing protein in all their neurons, resulting in adult-onset motor dysfunction that resembles what we see in SCA3 patients.
Neurodegeneration (damage/death of neurons) in C. elegans is monitored by tagging neurons with a marker that shines green under a specific type of light. The health of neurons is then assessed, making it possible to determine if neurodegeneration has occurred. The image above shows a healthy C. elegans neuron on the left, which appears intact, compared to a damaged C. elegans neuron on the right, which has a break (white arrowhead). Being able to distinguish between healthy and damaged neurons in C. elegans is very useful, as scientists can use this tool to test different ways of repairing or protecting neurons. If scientists are able to slow or prevent neurodegeneration in C. elegans, there is potential that such a discovery could eventually help treat human neurodegeneration, as well.
I hope this short summary has shown you that there is a massive amount of scientific potential in these tiny worms! Understanding the biology of C. elegans provides insight into human biology, like how neurodegeneration occurs and what we can do to stop it.
Written by Dr. David Bushart Edited by Dr. Sriram Jayabal
How can employment be made more accessible for ataxia patients? What barriers exist? A study of workers and non-workers with ataxia analyzes the benefit of employment, as well as how to reduce risk of injury.
A job can often become part of a person’s identity. When people meet for the first time, one of the first questions that often comes up is “what do you do for work?” While this question can be harmless, it can also be frustrating to non-workers, particularly to those who are actively looking for employment. This may include some patients with cerebellar ataxia.
It can be difficult to manage disease symptoms alongside the stress of a job. However, some patients may find that including a job as part of their routine can be helpful for physical and mental wellness. In these cases, it is important for ataxia patients to have access to fair employment. Despite these benefits, finding a job can prove quite challenging, and unfortunately, ignorant assumptions about the capabilities of workers with ataxia may make finding employment even harder. How can employment be made more accessible to ataxia patients who wish to work?
Determining the work capabilities of ataxia patients
Helping ataxia patients find work might have a significant benefit on their overall quality-of-life. Researchers in Italy designed a study to get a better idea about the capabilities of workers with ataxia and the barriers to employment that they face. The research team, led by Alberto Ranavolo, interviewed both workers and non-workers with ataxia. Importantly, the patients interviewed for this study had been diagnosed with different types of ataxia, including dominantly-inherited ataxias, Friedrich’s ataxia, and other ataxias with unknown causes. Within this group, 24 were currently workers and 58 were non-workers at the time of the study. This allowed the researchers to determine how characteristics such as age, gender, education, and duration of symptoms might impact the ability to work.