How does biotech address rare chromosomal abnormalities?


Humans usually have 23 pairs of chromosomes. But sometimes, in rare cases, an error during cell division can cause the cell to have an extra or missing chromosome, indicating a chromosomal abnormality.

Often, prenatal tests are done to detect chromosomal abnormalities. Amniocentesis is a diagnostic procedure in which the amniotic fluid that protects the fetus during pregnancy is tested for various disorders such as Down syndrome, Edwards syndrome and Patau syndrome. However, these tests are only offered if there is a higher chance of the baby having a genetic condition, because – although rare – the test is associated with a risk of miscarriage as well as the development of rhesus disease, also known as rhesus disease. hemolytic disease of the fetus and newborn (HDFN).

Recently, non-invasive prenatal tests (NIPT) have been introduced to identify trisomy 13, 18 and 21, as well as X chromosome abnormalities, through blood tests. NIPT is considered safe, as is the combined first trimester screening (CFTS), which is the conventionally used screening test.

As more accurate screening tests have been developed over the years to determine chromosomal abnormalities in the fetus, various clinical trials to treat these abnormalities are underway. Ahead of Rare Chromosome Disorder Awareness Day, observed on June 22, let’s see what biopharma companies are doing to treat chromosomal disorders.

Ultragenyx ongoing clinical trial for Angelman syndrome

Recently, the US-based company Ultragenyx was authorized protocol amendments by the US Food and Drug Administration (FDA) for its drug candidate that is being evaluated in a phase 1/2 study for Angelman syndrome. This allowed the company to align US dosage ranges with those used in cohorts outside the US, to speed study completion.

Angelman syndrome is a rare neurogenetic disorder caused by the simultaneous deletion of maternal chromosome 15 – and specifically the missing or silenced UBE3A gene – and the inheritance of its two paternal copies. An example of genome imprinting, this condition is characterized by developmental delays, sleep disturbances, seizures, balance and coordination problems, and occasionally, hyperactivity.

The drug candidate Ultragenyx GTX-102, which was granted Orphan Drug status in 2019, is an antisense oligonucleotide designed to inhibit UBE3A gene expression. Administered by injection into the spinal canal, GTX-102 works by re-activating paternal UBE3A allele expression in central nervous system (CNS) neurons. This has been associated with increased neurological symptoms in animal models of Angelman syndrome.

“The agreement on the protocol amendments allowed for a comparable range of doses across all geographic areas and allowed us to move quickly forward to completion of the study. We have started work immediately to activate multiple study sites in the US and plan to start enrollments as soon as possible,” said Scott Stromatt, senior vice president and chief medical officer of neurology clinical development at Ultragenyx. “We are eager to expand the US study to build on encouraging data demonstrating clinically important activity across a variety of functional domains affected by Angelman syndrome with an acceptable safety profile.”

According to results from last year’s provisional clinical trial data, the US Evaluation Scale of Change — a quantitative measure of the condition — investigated drugs based on five domains — sleep, behavior, communication, gross motor, and fine motor skills. Seven of the nine trial participants showed improvement from baseline in at least 3 of the 5 domains as well as overall scores.

As Ultragenyx begins to accelerate trials to treat Angelman syndrome, Australian company Neuren Pharmaceuticals is developing NNZ-2591, a candidate that targets the neurological symptoms of the disease.

Chromosomal disorders: Neuron Pharmaceuticals’ diverse channels

NNZ-2591, which was tested in a mouse model that mimics features of human Angelman syndrome, was found to improve motor performance, anxiety levels, cognition, and even negate the risk of seizures, over several weeks.

Currently in phase 2 clinical trials, the candidate is being evaluated in parallel with three other rare chromosomal disorders, namely Phelan-McDermid Syndrome, Pitt Hopkins Syndrome and Prader-Willi Syndrome.

Phelan-McDermid syndrome, a genetic disorder in which part of chromosome 22 is deleted – therefore also called 22q13 deletion syndrome – and is sometimes associated with a defective SHANK3 gene, causes developmental delays, and speech disorders, and patients tend to fall on the spectrum autism . Additionally, 40% of people with Phelan-McDermid Syndrome experience seizures that range from mild to severe.

For the treatment of symptoms, the clinical study NNZ-2591 Neuren Pharmaceuticals saw not only reduced symptoms in a mouse model but also observed a marked reduction – 83% – in the risk of seizures, a significant therapeutic advance. In addition, altered dendrite spine length in the brain and ERK protein hyperactivity – both features associated with this disease – are brought together during treatment.

The candidate also received the green light from the FDA to begin a phase 2 trial for the treatment of Prader-Willi Syndrome, a condition caused by the absence of genetic material on chromosome 15.

Targeting rare chromosomal disorders by managing symptoms

Meanwhile, Danish multinational healthcare company Novo Nordisk is also a key player in research into rare chromosomal diseases.

Turner syndrome is a disorder that arises because there is only one X chromosome instead of two. Affecting one in 2000 women born, this condition is associated with short stature, underdeveloped ovaries and an increased risk of infertility.

Short stature is caused by an inactive or deleted SHOX gene. To target this, Norditropin Novo Nordisk is the standard growth hormone therapy that was approved decades ago. And now, the company’s drug candidate Somapacitan is also under development. Delivered subcutaneously, Somapacitan is an endogenous growth hormone (GH) replacement that targets the somatotropin receptor in adults with growth hormone deficiency (GHD). Apart from Turner syndrome, which is currently in phase 3 trials, it is also being investigated to treat other growth disorders such as Noonan Syndrome and idiopathic short stature.

In addition to managing growth, to promote puberty and ensure healthy sexual development, estrogen and progesterone replacement therapy is a current treatment measure that combats the symptoms of Turner syndrome.

Other rare chromosomal disorders such as Patau syndrome, Edwards syndrome and Williams syndrome, although there are no drugs or targeted therapies, the specific symptoms of these conditions are treated by the healthcare sector. For example, for Edwards syndrome, which is characterized by an extra chromosome in the 18th pair, physiotherapy is the established treatment measure to promote progression. For babies who have difficulty swallowing because of a wobbled airway and poor coordination, and sometimes because of a cleft palate, a feeding tube helps with the problem.

For Williams syndrome, which is caused by spontaneous deletion of genetic material from chromosome 7, such as Edwards syndrome, managing symptoms is key. Cardiovascular problems are managed through frequent screening visits and in some cases people are prescribed beta blockers to control hypertensionalthough about 20% of people with Williams syndrome have surgery.

While efforts to improve the quality of life for those affected by this rare chromosomal disorder are under way, a cure for this condition may seem far-fetched today. However, with the rapid development of technology, such as artificial intelligence leading to drug discovery now, it is not unthinkable.

New technologies related to research of rare chromosomal disorders (Supported by IN-PART)


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