Research advances in treatment methods and drug development for rare diseases.

Han Q, Fu H, Chu X, Wen R, Zhang M, You T, Fu P, Qin J, and Cui T. (2022) Research advances in treatment methods and drug development for rare diseases. Frontiers in Pharmacology.

The World Health Organization specifies that an occurrence of 0.65 – 1.0% within the population is the criteria to consider a disorder a rare disease. An example of a rare disease is Rhizomelic chondrodysplasia punctata (RCDP) which is caused by a mutation in one of the plasmalogen biosynthetic pathway genes resulting in the inability to produce plasmalogens, a unique class of phospholipid. RCDP has a prevalence of ~1 in 100 000 live births and within North America there are fewer than 100 known cases. Within the population, each rare disease is very uncommon but together there are an estimated 400 million people with rare diseases globally. These consist of 6000 to 8000 different rare diseases and roughly 250 novel diseases are identified each year. A challenge with rare diseases is the ability to treat and cure them, with as low as 10% of rare diseases being properly treated while the others are only treated for their symptoms, like with RCDP. Here we summarize the work of Han et al, who reviewed drug development and current state of advances in treatment methods for these diseases.

One route that can be taken for the treatment of rare diseases is through drug development. Rare diseases are also called orphan diseases, thus drugs for these diseases are called orphan drugs. There is a shortage of orphan drug research and development caused by a number of factors. Firstly, the process to develop and get a new drug approved is quite long and very expensive, especially in comparison to other diseases. In addition, the patient group is small and this can discourage large pharmaceutical companies and investors from putting the time and money into researching, developing, and producing orphan drugs. Recent molecular biology developments and knowledge of the human genome has initiated further avenues in orphan drug development expanding from antibodies, protein, and traditional small molecules to small nucleic acid drugs, stem cell drugs, and enzyme protein degradation agents. Small nucleic acid drugs have been possible because of discoveries in nucleic acid modification and vector delivery technology. They are comprised of nucleotides with specific sequences and are mainly antisense oligonucleotides (ASO), small interfering RNA (siRNA), or microRNA (miRNA). Protein degradation targeting chimera (PROTAC) is a newer field of drug research and can alter targets that cannot be reached by small molecules or antibodies. The basis of PROTAC is to design small molecule compounds to solve the drug resistance problem that can occur with small molecule inhibitors by degrading the target protein. Small molecule drugs have been the main goal of pharmaceutical companies and computer aided screening and advances in chemistry and biology have shortened the timeline needed to discover and design new drugs. Specifically with rare diseases, targeted screening and better-quality disease models has made small molecule drugs very successful.

As few as 10% of rare diseases are properly treated and many require more than just pharmaceutical therapies to treat and, hopefully, cure the disease. A common challenge with rare diseases is that accurate diagnosis and treatment are difficult since genetic defects are often the cause. If an orphan drug is not successful or feasible, some other possible treatment methods for rare diseases are diet therapy, surgery, and bone marrow transplantation, as well as some newer techniques including gene therapy, stem cell therapy, antibody therapy, and enzyme replacement therapy. Gene therapy is a technique used to treat or prevent diseases by altering human genes and since many rare diseases are caused by mutations in a single inherited gene, this method can be very effective. The first gene therapy drug was approved by the FDA in 2017 and was developed by Spark Therapeutics’ Luxturna. They created Voretigene Neparvovec to treat Leber congenital amaurosis which is an inherited disorder that causes progressive blindness induced by a mutation in the retinal pigment epithelium-specific 65 kDa (RPE65) gene. This therapy is given once through subretinal injection and, although it does not cure the condition, it does significantly improve vision by replacing the mutated gene with an intact version. Gene therapy has been a breakthrough therapy for many rare diseases, but the technology is only possible to treat the gene target in one specific tissue and not systemically. Stem cell therapy alters or supports the immune system through using human cells such as fetal liver cell transplantation, bone marrow transplantation, peripheral hematopoietic stem cell transplantation, or umbilical cord blood transplantation. For example, when people with leukemia or lymphoma are treated with chemotherapy, the treatment does not discriminate between the growing cancer cells and hematopoietic stem cells in bone marrow and ends up killing both cell types. A stem cell treatment can reintroduce functional stem cells into the host’s body and will help generate an immune response that kills off the cancer cells. Antibody therapy is a type of immunotherapy that monospecifically binds monoclonal antibodies to certain cells or proteins with the goal of stimulating the person’s immune system to a specific target. A monoclonal antibody could be bound to cancer cells so that the body can better recognize the target cell and destroy it. Enzyme replacement therapy (ERT) can be used for rare diseases where an enzyme is missing or deficient and is supplied by infusions of the enzyme purified from human or animal tissue or blood or produced by novel recombinant techniques. ERT can be used to treat some lysosomal storage diseases such as Gaucher disease, Fabry disease, and Pompe disease through increasing the concentration of the enzyme that the person is lacking, however it does not correct the genetic defect causing the disease.

Individually, rare diseases have a very small prevalence within the population compared to other diseases, but together affect around 400 million people which is nearly 5% of people globally. With such a large number of people impacted by these diseases and more being identified every year, it is essential that research into the etiology, pathology, and appropriate treatment methods for rare diseases is ongoing. Groundbreaking technological advancements in the last few decades regarding the human genome, genetic sequencing, and employing this knowledge in designing therapies and treatments has greatly changed the landscape for rare disease treatment but continued work in this area is essential to keep up with the new rare diseases found each year.