Translational science of rare diseases最新文献

Undiagnosed and rare conditions are collectively common and affect millions of people worldwide. The NIH Undiagnosed Diseases Program (UDP) strives to achieve both a comprehensive diagnosis and a better understanding of the mechanisms of disease for many of these individuals. Through the careful review of records, a well-orchestrated inpatient evaluation, genomic sequencing and testing, and with the use of emerging strategies such as matchmaking programs, the UDP succeeds nearly 30 percent of the time for these highly selective cases. Although the UDP process is built on a unique set of resources, case examples demonstrate steps genetic professionals can take, in both clinical and research settings, to arrive at a diagnosis for their most challenging cases.

Non-motile ciliopathies (disorders of the primary cilia) include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, as well as multisystem disorders Joubert, Bardet-Biedl, Alström, Meckel-Gruber, oral-facial-digital syndromes, and Jeune chondrodysplasia and other skeletal ciliopathies. Chronic progressive disease of the kidneys, liver, and retina are common features in non-motile ciliopathies. Some ciliopathies also manifest neurological, skeletal, olfactory and auditory defects. Obesity and type 2 diabetes mellitus are characteristic features of Bardet-Biedl and Alström syndromes. Overlapping clinical features and molecular heterogeneity of these ciliopathies render their diagnoses challenging. In this review, we describe the clinical characteristics of individual organ disease for each ciliopathy and provide natural history data on kidney, liver, retinal disease progression and central nervous system function.

Organic acidemias and urea cycle disorders are ultra-rare inborn errors of metabolism characterized by episodic acute decompensation, often associated with hyperammonemia, resulting in brain edema and encephalopathy. Retrospective reports and translational studies suggest that N-carbamylglutamate (NCG) may be effective in reducing ammonia levels during acute decompensation in two organic acidemias, propionic and methylmalonic acidemia (PA and MMA), and in two urea cycle disorders, carbamylphosphate synthetase 1 and ornithine transcarbamylase deficiency (CPSD and OTCD). We established the 9-site N-carbamylglutamate Consortium (NCGC) in order to conduct two randomized double-blind, placebo-controlled trials of NCG in acute hyperammonemia of PA, MMA, CPSD and OTCD. Conducting clinical trials is challenging in any disease, but poses unique barriers and risks in the ultra-rare disorders. As the number of clinical trials in orphan diseases increases, evaluating the successes and opportunities for improvement in such trials is essential. We summarize herein the design, methods, experiences, challenges and lessons from the NCGC-conducted trials.

The field of regenerative medicine is growing rapidly with the introduction of new therapies that have the potential to treat and cure serious medical conditions, including rare diseases, for which there are no available treatments. In the United States, the development of novel medical products is regulated and guided by the Food and Drug Administration (FDA). As scientific and technological advances are discovered and adopted by the medical industrial enterprise, the FDA's implementation of policies that create a climate conducive to safe development and rapid availability of novel medical products is one of the pillars which support the Agency's mission of protecting and promoting the public health. With advancements in cell modifications and tissue engineering, innovative creation of biomaterials, adoption of three-dimensional bioprinting, and rapid development of human genome editing technologies, the need for Agency's work in ensuring that its science-based policies remain relevant and helpful in facilitating the availability of new treatments to the most vulnerable populations of patients becomes more pressing than ever before. In December 2016, Congress amended section 506 of the Food, Drug, and Cosmetic (FD&C) Act [21 U.S.C. 356] by adding a new section 506(g), which defines the categories of products considered to be regenerative medicine therapies. As further described by FDA [1], regenerative medicine therapies are considered to include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies, as well as gene therapies, including genetically modified cells that lead to a durable modification of cells or tissues. The development and approval of regenerative medicine therapies are regulated by FDA's Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER). In this review article, we present practical considerations for investigating regenerative medicine therapies intended for the treatment of rare diseases. The material presented may be useful to researchers who are undertaking the challenging task of finding and delivering new treatments for those in need.