Scientists discover rare genetic condition that attacks kids’ immune systems
Shire's Hunter Syndrome Cognitive Impairment Drug Fails
Shire's attempts to develop a drug for cognitive impairment from the rare inherited disease Hunter Syndrome has failed to produce results.
The company's Elaprase (idursulfase) is already approved for Hunter syndrome, and the experimental drug SHP609 was an attempt to produce a drug to treat cognitive impairment associated with the disease.
Elaprase, an enzyme replacement therapy, cannot cross the blood-brain barrier, so the new formulation is injected through the spinal column.
SHP609 was supposed to correct the deficiency in the iduronate-2-sulfatase enzyme in the CNS and prevent the cognitive decline seen in some Hunter Syndrome cases.
Sadly, Shire said the phase 2/3 study did not meet either its primary or secondary endpoints.
The primary endpoint evaluated the difference in cognition between the SHP609-treated and control groups, as measured by change from baseline in General Conceptual Ability (GCA) scores in children with Hunter syndrome after 12 months of treatment.
The key secondary endpoint evaluated the difference between the SHP609-treated and control groups as measured by the change from baseline in Adaptive Behaviour Composite (ABC) score.
[caption id="attachment_35398" align="alignnone" width="251"] Howard Meyer[/caption]
Howard Mayer, senior vice president and global head of R&D (ad-interim), Shire, said: "Shire is disappointed that the top-line data from this study did not meet the primary and key secondary endpoints and remains committed to patients and families living with MPS II."
"We are grateful to the children, their families and healthcare providers for participating in this challenging trial and will continue our ongoing dialogue with the community as we conduct an analysis of the full data set. Further analysis of the data will be presented at forthcoming congresses."
Last month Sangamo Therapeutics made history by attempting to treat Hunter Syndrome by attempting to edit a patient's genes, the first time the technique had been attempted in a clinical trial.
Groundbreaking Gene Therapy Trial For Hunter Syndrome Opens
The UK regulatory authorities have approved the first ever trial of a revolutionary gene therapy for young children diagnosed with Hunter syndrome, a devastating rare lysosomal storage disorder.
Five children under one year of age with the condition also known as mucopolysaccharidosis type II (MPS II) will be treated with autologous hematopoietic stem cell (HSC) gene therapy.
The children will continue to receive enzyme replacement therapy during treatment, but once the gene therapy begins to work, the research team say part of the trial aims to remove the need for weekly enzyme replacement therapy over the child's lifetime, while the other aim is to safely target the brain disease suffered by these patients.
The combined phase 1 and 2 clinical trial initiated by University of Manchester researchers, is now open to recruitment. AVROBIO, the previous funders of the program, have returned the license to The University of Manchester.
The study will be carried out at Royal Manchester Children's Hospital (RMCH) in collaboration with the Manchester Centre for Genomic Medicine at Saint Mary's Hospital – both part of Manchester University NHS Foundation Trust (MFT), will trial the drug for the treatment for this rare inherited disorder, which was developed over eight years by Brian Bigger, Professor of Cell and Gene Therapy at The University of Manchester.
Professor Bigger and his team this month published a paper in Molecular Therapy clinical Methods which validates the proof-of-concept outcomes findings in mice, providing further long-term efficacy data.
The trial aims to recruit up to five patients with severe MPS II who are aged between 3 months and 12 months at time of consent. Inclusion criteria are for children in the above age range with a confirmed diagnosis of severe MPSII who may already be on enzyme replacement therapy but have not yet developmentally declined.
It will be a 24-month, single-arm, open label study which will evaluate the HSC gene therapy's safety and tolerability, as well as its pharmacodynamic and clinical efficacy.
Children with severe Hunter syndrome cannot properly break down complex sugar molecules and have widespread symptoms including rapid and progressive learning and memory problems, heart and lung dysfunction, hyperactivity and behavioural problems, bone and joint malformations and hearing impairment.
The UK Medicines and Healthcare Products Regulatory Agency (MHRA), Research Ethics Committee (REC), and Health Research Authority (HRA) have all approved the clinical trial application that was submitted by The University of Manchester in August 2022.
The clinical trial will be led by Professor Rob Wynn, Consultant Paediatric Haematologist at RMCH, together with Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at Saint Mary's Hospital, and Professor Bigger at The University of Manchester. The University of Manchester will act as trial sponsor.
Children with Hunter syndrome have a missing gene, meaning they cannot produce an important enzyme called iduronate-2-sulfatase or IDS. The gene therapy works by collecting HSCs from the patient and inserting a working copy of the gene into the HSCs using a lentiviral gene therapy vector. The modified HSCs are then infused back into the patient to engraft in the bone marrow. Following successful engraftment of modified HSCs in the bone marrow, these cells start to produce daughter blood cells which contain the IDS gene and enzyme which are distributed throughout the body, including the brain.
Professor Bigger said: "This is a next generation stem cell gene therapy approach, which allows transit of the IDS enzyme into the brain. The newly inserted IDS gene produces an IDS enzyme that contains a proprietary ApoEII-tagged sequence, which can bind to ApoE-dependent receptors on the blood brain barrier, and move enzyme into the brain more efficiently, thus potentially normalizing brain pathology.
"This should speed up delivery of enzyme to the brain, where it is most needed as we can leverage all the enzyme produced by the blood to do this rather than just relying on the engraftment of monocyte cells from the blood into the brain."
He added: "We're very excited by the pre-clinical studies we carried out in mice, which showed the potential to correct disease in the body and normalize brain pathology.
"Mice with Hunter syndrome treated with the HSC gene therapy showed dramatic improvement in their condition, including normalization of working memory problems, and skeletal features such as the cheekbone dimensions and the width of the humerus and femur bones."
The trial is the culmination of a more than 15-year collaborative effort with Professor Wynn and Professor Jones at MFT to develop HSC gene therapies for neurological lysosomal disorders and is now the second potential neurological gene therapy that this collaborative team has brought into the clinical setting.
Bob Stevens, chief executive of the MPS society said: "This ground-breaking trial initiated by The University of Manchester offers the possibility of new treatment options in the future for patients with the severest form of MPSII Hunters. We look forward to hearing the outcome of this trial, with cautious optimism and hope that science will offer the chance of a 'Rare Life Lived Better'."
What Is Sanfilippo Syndrome?
Sanfilippo syndrome, also known as mucopolysaccharidosis type III, is a rare life-threatening disorder that interferes with metabolism. While it doesn't have a cure, some symptoms can be treated to manage this condition. Here's everything you need to know.
Sanfilippo syndrome is a genetic disorder that affects your child's metabolism and brain development. A person with this condition lacks a key enzyme that breaks down a type of waste produced by the body.
Enzymes are proteins that help you break down or metabolize various substances including food materials such as sugar. Within your cells, they are located in sacs called lysosomes. These lysosomes are affected by Sanfilippo syndrome, which is why this disorder is regarded as a lysosomal storage disease.
Specifically, Sanfilippo makes the body unable to break down a molecule called heparan sulfate — a natural cellular substance usually metabolized and recycled through enzyme action. As a result, heparan sulfate starts to build up in the cells and stops them from functioning correctly. This eventually leads to organ damage, growth disorders, behavioral problems, and severe neurological deterioration over time.
Sanfilippo syndrome is seen in 1 in 70,000 births in the U.S., and children with it have a life expectancy of 10 to 20 years, on average. While it's considered a rare disease, having a family history of it increases the risk for your child.
Normally, four enzymes break down heparan sulfate, so Sanfilippo syndrome has four types based on the missing enzyme type. Some types are less aggressive than others, and life expectancy varies, too. Of course, each child is unique and lifespan estimates vary based on different factors.
Sanfilippo syndrome type A
This type is the most common and also the most severe. Children with this type will usually lose their ability to walk and talk early. Type A progresses rapidly, so advanced Sanfilippo syndrome symptoms appear at an earlier age. Children with type A have the shortest life expectancy — 15 years on average — of all four types of the syndrome.
Sanfilippo syndrome type B
This type is less common and usually progresses more slowly than type A. Research shows that children with type B have an average lifespan of about 19 years.
Sanfilippo syndrome types C and D
These two are the least common kinds of Sanfilippo syndrome, with type D being the rarest of all four types. They generally progress more slowly than types A and B.
Children with types C or D may hold onto some motor skills, such as walking and talking, longer than those with the other types. Children with type C may live to about 23 years of age. Type D is so rare that there is too little evidence to predict an average lifespan.
Early symptoms often appear from birth to age 2, but sometimes parents don't notice the symptoms or doctors confuse them for other conditions.
Early Sanfilippo syndrome symptoms include:
Symptoms worsen as the disorder progresses. Children with Sanfilippo syndrome lose their ability to walk, talk, eat, and hear over time. Sleep and behavioral issues also worsen.
Late symptoms of Sanfilippo syndrome include:
Sanfilippo syndrome eyebrows
Parents might notice that their child with Sanfilippo syndrome looks different than their siblings. Large eyebrows with more hair than expected are a unique feature of this condition. These facial features become more pronounced as children with Sanfilippo syndrome age. Their eyebrows thicken and may even grow across their forehead into a single brow.
All types of Sanfilippo syndrome progress through three phases. The timing of each phase varies, and symptoms may overlap from one phase into the next. The rate of progression through the phases can be rapid for some and slow for others.
In very rare cases, your child might not have any obvious symptoms of the disorder during childhood and doesn't progress through the stages until they are a teenager or adult. Doctors call this an "attenuated" form of the syndrome.
Phase I takes place between the ages of 1 and 3 years when early symptoms appear. You may notice your child's speech and cognitive (learning and thinking) development slows down.
Phase II begins around the ages of 3-4 years. Behavioral and sleep challenges worsen during this phase. Hyperactivity, impulsivity, anxiety, and autism-like behaviors may become extreme during this phase. Learning and thinking abilities decline, too.
Phase III typically starts in the teen years with the onset of dementia-like symptoms that progress to a vegetative state — your child is awake but unaware and unable to interact with their surroundings. Children in this phase lose their ability to move, communicate, and eat.
Most doctors don't test for Sanfilippo syndrome during its early stages, as it's a rare disease with symptoms that are easily confused for other conditions such as autism or ADH. But early diagnosis is important to access clinical trials and get the best support and services for your child.
If your child has a combination of developmental delays, birth defects, and other early symptoms, their doctor may suggest genetic or metabolic testing.
But the first screening test for Sanfilippo syndrome is usually a urine test called the Urine MPS Screening Analysis. If there are high levels of heparan sulfate in your child's pee, it may mean they have Sanfilippo syndrome.
Doctors confirm a Sanfilippo syndrome diagnosis with a blood test that checks enzyme activity. Your doctor may recommend this blood test if getting a urine sample from your child is difficult or not possible.
There's no cure for Sanfilippo syndrome. Instead, doctors focus on providing supportive care — care that eases symptoms and helps a child with Sanfilippo have the best possible quality of life for as long as possible.
Clinical trials explore different experimental medications and treatments such as enzyme replacement therapy (ERT) and gene therapy. While these options aren't FDA-approved, you may find that taking part in a clinical trial is the best option for your child. Other options include:
Speech-language therapy
Speech delay is a common early Sanfilippo symptom. A speech-language therapist will work with you and your child to improve and maintain verbal and nonverbal communication. This includes using tools such as picture cards or electronic tablet apps that work with touch or eye gaze.
Feeding therapy
Chewing and swallowing become more difficult as Sanfilippo syndrome progresses. Because of this, many children have trouble eating safely. A speech therapist who specializes in feeding therapy will observe how your child eats. They may recommend a swallow study (a special X-ray) if your child has choking episodes. The feeding therapist will come up with a plan to support your child's ability to eat and drink by mouth for as long as possible.
Physical therapy
Children with Sanfilippo syndrome lose their ability to move and walk. A physical therapist can help your child maintain their strength and ability to move for as long as possible by working on things like balance, flexibility, walking skills, and sitting positions.
As your child becomes less mobile, they may need medical equipment to help them get around, such as a wheelchair or specialized stroller. A physical therapist can help you access that equipment.
Occupational therapy
Orthopedic problems, such as stiff joints, are a common later symptom of this condition. An occupational therapist can help your child maintain fine motor skills they need for feeding, dressing, coloring, and playing with toys. They may also suggest activities and strategies to meet your child's sensory needs.
Sanfilippo syndrome can't be prevented, but you can try to minimize risks by checking your family history. Your child is at risk of getting Sanfilippo syndrome if both you and your partner carry the affected gene. People who are planning to get pregnant can get tested to see if they are a carrier for Sanfilippo syndrome first. There are several tests available to order through companies online or through your doctor.
Another good way of minimizing Sanfilippo syndrome risk as much as possible is to check if your newborn screening has a relevant test for it.
You might feel overwhelmed when your child is first diagnosed with Sanfilippo syndrome.
Connect with organizations such as Cure Sanfilippo Foundation, which is a great place to find information, experts, resources, and other parents of children with this rare condition.
Learn about resources and take steps to support your child's unique needs. This may include:
Your insurance carrier or health care system may have a care coordinator or case manager — often a nurse — to help meet your child's needs, especially as they become more complex over time. They can help with accessing therapies, medical supplies, and other resources for support.
Children with rare conditions such as Sanfilippo syndrome have many unique needs. Here are some ways to support different areas of your child's life:
Nutritional support
There's no single diet that doctors recommend for children with Sanfilippo syndrome. A dietitian can help make sure your child is getting enough calories by eating the right foods. When chewing and swallowing make eating dangerous or impossible, talk with your doctor and dietitian about feeding tube placement — a tube connected directly to the stomach for liquid food. This option depends on many different factors, and it may or may not be the best choice for your child.
Caring for your child's unique — and sometimes complicated — needs is a big job. And it's normal to feel overwhelmed, stressed, or burnt out.
To help manage your mental load, carve out time to take care of yourself. Sometimes, this may seem impossible, but having trusted support people in place can make it easier to ask for help when you need it.
Connect with others in the Sanfilippo community. Learn from and share with others who are dealing with similar challenges. Support from your network may help you deal with challenges during especially difficult times.
It's important to talk to your doctor about overwhelming feelings of anxiety, depression, or grief. Mental health counselors or therapists can help you manage challenging feelings.
Sanfilippo syndrome is a rare genetic disorder that causes brain damage because the body can't break down certain sugars. Symptoms usually start in early childhood, with developmental and speech delays, behavior issues, and loss of skills such as walking and talking. There is no cure, but early diagnosis can help you manage your child's symptoms. Connect with support groups and specialists who can help you create a health care team to meet your child's needs.
What is the lifespan of someone with Sanfilippo syndrome?
It depends on the type of Sanfilippo syndrome. Type A has the shortest life expectancy, about 15 years, while the lifespan of someone with type B or C may range from 19 to 23 years.
What are the first signs of Sanfilippo syndrome?
The first signs include speech and developmental delays, coarse facial features (including a prominent forehead and eyebrows, and full nose and lips), an unusually large head, and behavioral issues similar to autism and ADHD.
What is the oldest someone has lived with Sanfilippo?
Attenuated Sanfilippo syndrome is a very rare, slowly progressing form of the condition. Some reports suggest that people with this form of the syndrome may live to their 40s, 50s, or 60s.
What are the final stages of Sanfilippo syndrome?
The final stage of Sanfilippo syndrome involves dementia-like symptoms, including loss of movement, communication, and the ability to eat. These complications may lead to early death.
Do kids with Sanfilippo talk?
Yes. While speech delays are common, children with Sanfilippo syndrome can talk. As the disorder progresses, they lose their ability to talk.
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