Spinal muscular atrophy (SMA) expert Basil T. Darras, MD, is optimistic about treatment advances and the possibility of a future cure, according to a recent interview in which he shared his thoughts on current SMA therapeutic approaches and care.
Darras is a professor of neurology (pediatrics) at Harvard Medical School and director of the SMA Program at Boston Children’s Hospital, where he is also chief of the Division of Clinical Neurology in the Department of Neurology.
He directs two multidisciplinary clinical programs that provide diagnostic evaluation and treatment for children with neuromuscular diseases and investigate new therapies for SMA patients. Darras edited the only major, comprehensive textbook on pediatric neuromuscular disorders, and authored more than 190 peer-reviewed publications and 80 book chapters.
The interview, “Spinal muscular atrophy type I and the dual role of viruses: An interview with Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School,” appeared in the journal Experimental and Therapeutic Medicine.
SMA is caused by mutations in the SMN1 gene, leading to a deficiency or complete absence of the SMN1 protein, which is key for motor neurons’ survival and proper motor function. Expression of the SMN2 gene also generates the SMN protein, but at much lower levels.
Early genetic diagnosis is essential to providing better care and reducing parental stress. A recent recommendation by the U.S. Department of Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children for universal newborn screening is evidence of the growing consensus between experts, advocacy groups, and pharmaceutical companies that the disease should be detected before symptoms start to improve treatment effectiveness.
“This is of great interest as this will help identify pre-symptomatic individuals in the general population enabling us to initiate early therapy for children with SMA,” Darras said.
He believes that genetic counseling for parents of children with SMA, is “a very positive issue that should be immediately explained and proposed to these parents. … There is a 25% risk that each offspring of two carrier parents will be affected with the autosomal recessive inherited forms of SMA.”
SMA type 1, the most common and severe disease type, progressively affects all physical movement, including walking, swallowing, and breathing. These children are “ ‘non-sitters’; they never achieve the ability to sit independently,” according to Darras. Symptoms typically arise before 6 months of age and lifespan is reduced, although respiratory and nutritional supportive care have brought relevant improvements recently, he said.
Diagnosis of SMA type 1 is currently based on detailed physical and neurological examinations. Children present severe muscle weakness, poor muscle tone, impaired reflexes, lack of motor development, and a twitching of the tongue. Abnormal breathing, known as abdominal breathing, as well as a bell-shaped chest are also evident.
Although atypical cases may require other tests, the combination of the breathing, tongue, and reflex alterations are indeed very strongly suggestive of SMA type I, Darras said.
Diagnosis of SMA type 1 is devastating news to both children and parents, who will have several doubts and concerns with difficult medical answers. Pediatric neurologists — who have to report the positive result of the genetic test — along with medical professionals and primary care physicians are also faced with a challenging situation.
Because SMA type 1 is a rare disease, primary care pediatricians usually only see one case during their entire career, Darras said. In order to avoid diagnostic delays, “medical training is essential,” he urged. Having the opportunity to examine children with SMA during medical education is “undoubtly unforgettable.”
“The early diagnosis and employment of management interventions for these children are indeed essential and will become even more important in the future as more treatments for SMA become available,“ Darras said.
However, ethical challenges in clinical trials, especially regarding placebo treatment to patients, and their limited access to specialist healthcare services still represent important obstacles for investigative treatments and optimal care.
Darras listed three possible management options for the progressive loss of respiratory function, the No. 1 cause of mortality in children with SMA type 1: no respiratory support, non-invasive ventilation with a Bi-PAP machine, and tracheotomy with mechanical ventilation.
Choosing an option should be done after timely discussion with parents and care providers and depends on the patient’s respiratory status, available medical services, and “how aggressive [parents] want to be in treating the child,” Darras said. Palliative care is an additional option for the most severely affected, he added.
In particular, non-invasive ventilation improves chest wall and lung development and may reduce lung infections, which are prevalent in these children. When combined with nutritional support, non-invasive ventilation can prolong survival. Darras mentioned the Critical Care, Anesthesia Perioperative Extension (CAPE) and Home Ventilation Program offered at Boston Children’s Hospital, which provides services to optimize care at home, facilitate hospital-based care, and ultimately prevent more admissions to the hospital.
Darras said that he personally does not support tracheostomy for long-term mechanical respiratory support in children with SMA type 1.
“The quality of life of these children should remain our main target. So, definitely, their long-term multidisciplinary health care should be home-based,” he said.
Acute fever should be immediately treated with broad-spectrum antibiotics. “Any child with SMA type I is at risk to develop pneumonia which, once established, is very difficult to treat,” he said. Respiratory infections with RSV (respiratory syncytial virus) and seasonal influenza viruses are common and may be life-threatening. “Prevention of these viral infections is strongly recommended,” Darras added, and includes influenza vaccination and RSV prophylaxis.
An additional focus should be put on nutritional care. Darras said that gastrostomy — the creation of an artificial external opening into the stomach for nutritional support — may also reduce long-term aspiration events, but should be considered early in disease course. Consultation with a specialized dietitian knowledgeable in SMA may also help.
The U.S. Food and Drug Administration approved Biogen’s Spinraza (nusinersen) for the treatment of SMA types 1-3 in December 2016. This decision was followed by a similar 2017 approval in the European Union. Although Spinraza may improve motor function of patients, it is a treatment, not a cure, Darras said.
He and Boston Children’s Hospital have been involved in Spinraza’s clinical trials since their start in 2011. The hospital was the first to enroll a child with SMA type 1 in the ENDEAR Phase 3 trial (NCT02193074), in 2014. Both this study in SMA type 1 and the CHERISH Phase 3 trial (NCT02292537) in children with the milder SMA type 2 showed that treatment with Spinraza led to significant improvements in motor function. Further benefits in achieving developmental milestones, quality of life, and survival were also noted.
Other treatment candidates are being tested in clinical trials, including AveXis gene therapy AXVS-101, which uses a modified, non-infectious virus called adeno-associated virus type 9. This therapy’s potential is supported by results of a Phase 1 study (NCT02122952) that addressed the safety and effectiveness of intravenous AVXS-101 in 15 type 1 SMA infants.
“Improved outcomes may soon be forthcoming,” Darras said.
Among the treatments being tested, the investigator highlighted RG7916, an oral compound developed by Roche, PTC Therapeutics, and the SMA Foundation that, similar to Spinraza, increases the production of normal SMN proteins from the SMN2 gene. This treatment candidate “is really quite promising,” Darras said, and has shown good results regarding safety and tolerability so far.
“The future is full of hope and I am very optimistic that we will have a number of treatments for SMA. The cure of SMA does not seem as far into the future as it looked 5 or 10 years ago,” Darras said. “Gene therapy using viral vectors is expected to offer an ‘one and done’ therapy and possibly cure the disease if administered early in life before symptoms appear.
“And it is really interesting that viruses, which at the moment can be the cause of death in these children, with proper genetic engineering, could be used for their treatment in the future.”