Comparative Study of Strategies for Management of Duchenne Myopathy (DM)

Myopathy Clinical Trial

Official title:

A Comparative Study of Strategies for Management of Duchenne Myopathy in Assiut University Children Hospital

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03633565
• Other study ID #: smdmauch
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: September 2018
• Est. completion date: November 2021

Study information

• Verified date: August 2018
• Source: Assiut University
• Contact: Duaa Mahmoud, Assistant professor
• Phone: 01223112124
• Email: duaa-raafat[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

1. Comparing different lines of treatment of Duchenne Myopathy (DM) and assessment of new lines of treatment (mesenchymal stem cell, phosphodiesterase inhibitors) in reducing the impact of disability in the patients with Duchenne Myopathy and slowing the progression of cardiomyopathy

2. Upsetting and implementation of the best treatment plan for those children with Duchenne myopathy which is suitable for the available resources in Assiut University Children Hospital

Description:

Duchenne muscular dystrophy(DMD) is the most commonly inherited pediatric muscular disorder. It is an X-linked genetic progressive and degenerative myopathy characterized by progressive weakness, which can lead to loss of motor functions in puberty as well as cardiac,respiratory involvement and premature death. The disease is one of a group of myopathies that differ depending on the degree of severity and the affected muscle types. It occurs at a rate of approximately 1:3500 male births and arises due to spontaneous mutations in the Dystrophin gene (locus Xp21.2); 65% of causative mutations are intragenic deletions, 6-10% are intragenic duplications and 30-35% are point mutations (along with other sequence variations). The disease is caused by a deficiency of Dystrophin or the synthesis of functionally impotent Dystrophin, a critical protein component of the Dystrophin glycoprotein complex acting as a link between the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. A consequence of Dystrophin glycoprotein complex inefficiency is muscle fragility, contraction-induced damage, necrosis and inflammation.

Glucocorticoid can prolong ambulation by 2 to 3 years, reduce scoliosis, and temper pulmonary and cardiac decline in the second decade of life. However, glucocorticoids causes well-known side effects, which are intolerable in more than 25% of patients. Thus, a disease-specific treatment is a major unmet need. Investigators have proposed various possibilities for the beneficial effects of corticosteroid based mainly on observations in mouse models of muscular dystrophy and on a limited number of studies in patients.

These possibilities include

1. Reducing cytotoxic T lymphocytes

2. Increasing Laminin expression and myogenic repair

3. Retarding muscle apoptosis and cellular infiltration

4. Enhancing Dystrophin expression

5. Affecting neuromuscular transmission

Some patients with Duchenne Myopathy treated early with steroids appear to have an improved long-term prognosis in muscle, myocardial outcome, and can help keep patients ambulatory for more years than expected without treatment. One protocol gives prednisone (0.75 mg/kg/day) for the 1st 10 days of each month to avoid chronic complications. Deflazacort, administered as 0.9 mg/kg/day, may be more effective than prednisone. The American Academy of Neurology and the Child Neurology Society recommend administering corticosteroids during the ambulatory stage of the disease.Published recommendations suggest starting therapy between 2 and 5 years of age in boys whose strength has plateaued or is declining, but earlier treatment may be more beneficial.

Skeletal muscle has a great capacity to regenerate following muscle wasting caused by trauma or disease.This regenerative potential is attributed primarily to skeletal-muscle resident stem cells called satellite cells. In Duchenne Myopathy, satellite cells are exhausted following many rounds of muscle degeneration and regeneration. Hence, satellite cells and their progeny (myoblasts) have been considered as a promising candidate for cell replacement therapy for DMD and other types of muscle disease. Small quantities of adult stem cells exist in most tissues throughout the body where they remain quiescent for long periods of time prior to being activated in response to disease or tissue injury. Adult stem cells can be isolated from cells of the hematopoietic, neural, dermal, muscle and hepatic systems. Adult stem cells give rise to cell types of the tissue from which they originated, but according to scientific reports, they can differentiate into lineages other than their tissue of origin, e.g. transplanted bone marrow or enriched hematopoietic stem cells (HSCs) were reported to give rise to cells of the mesoderm, endoderm and ectoderm.

Two main types of stem cells usually derived from adult bone marrow are HSCs and mesenchymal stem cells (MSC). They can sometimes be obtained from fat, skin, periosteum, synovial membrane and muscle as well. MSCs are multipotent and capable of differentiating into several connective tissue types including osteocytes, chondrocytes, adipocytes, tenocytes and myoblasts. They can also impose an additional anti-inflammatory and paracrine effect on differentiation and tissue regeneration via cytokine pathways and have anti-apoptotic features. These genetically determined pluripotent cells may be easily isolated from bone marrow because they have membrane proteins (marker called cluster of differentiation (CD34 +) and specific marker STRO-I). Compared with pluripotent embryonic stem cells or induced pluripotent stem cells, mesenchymal stem cell have a greater biosafety profile and lower risk of tumorigenicity, and perhaps that is why numerous -mesenchymal stem cell based therapies have made it to the clinical trial stage. Stem cell based therapies for the treatment of Duchenne Myopathy can proceed via two strategies.

The first is autologous stem cell transfer involving cells from a patient with Duchenne Myopathy that are genetically altered in vitro to restore dystrophin expression and are subsequently re-implanted. The second is allogenic stem cell transfer, containing cells from an individual with functional dystrophin, which are transplanted into a dystrophic patient.

Intramuscular route of administration can be considered most appropriate as muscular dystrophy is primarily a muscle disease. The cells can be injected in several points in the muscle alternatively they can be injected in the motor point of the muscle. A motor point is the point at which the motor branch of the innervating nerve enters the muscle. It is the point with the highest concentration of motor endplates and myoneural synapses. Due to high numbers of neuromuscular junctions at this point, a muscle contraction can be easily elicited using minimal electric stimulus. Motor points can therefore be identified as superficial points directly over the points on the muscles with help of external electrical stimulation. Limitation of this method is that only superficial muscles can be stimulated using this method.

In an open study, Sharma and colleagues demonstrated the efficacy of autologous bone marrow mononuclear transplantation by intramuscularly to patients with Duchenne Myopathy, Becker muscular dystrophy and limb girdle muscular dystrophy. However, they did not provide the molecular diagnosis of these dystrophies. No significant adverse events were noted. An increase in trunk muscle strength was seen in 53% of the cases, 48% showed an increase in upper limb strength, 59% showed an increase in lower limb strength and approximately 10% showed improved gait. Eighty seven percent of 150 patients had functional improvement upon physical examination and electromyogram studies after 12 month.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 45
• Est. completion date: November 2021
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 5 Years to 15 Years

Eligibility

Inclusion Criteria:

• Diagnosis of DMD confirmed by electromyogram (EMG) , Creatine phosphokinase (CPK) level and/ or DNA analysis or muscle biopsy.

• Male patients

• Age 5-15y.

• Ambulatory (loss of ambulation was only seen in those with baseline 6 Minute Walk Distance {6MWD} <325 meters.)

• No clinical evidence of heart failure.

Exclusion Criteria:

• Female patients

• Any injury which may impact functional testing, e.g. upper or lower limb fracture.

• hypertension, diabetes,

• Wheelchair bound.

• Cardiac rhythm disorder, specifically: rhythm other than sinus, supraventricular tachycardia (SVT), atrial fibrillation, ventricular tachycardia.or heart failure (left ventricle ejection fraction {LVEF < 50%}.

• Continuous ventilatory support.

• Liver disease (acute, chronic liver disease)

• Renal impairment

Related Conditions & MeSH terms

• Muscular Diseases
• Myopathy

Intervention

Drug:
• Sildenafil (Phosphodiesterase inhibitors)
tablet 25mg
• Prednisolone (Steroids)
tablet 20 mg

Procedure:
• Mesenchymal stem cell transplantation
stem cell transplantation intramuscular

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

References & Publications (18)

Emery AE. The muscular dystrophies. Lancet. 2002 Feb 23;359(9307):687-95. Review. — View Citation

Fukudome T, Shibuya N, Yoshimura T, Eguchi K. Short-term effects of prednisolone on neuromuscular transmission in the isolated mdx mouse diaphragm. Tohoku J Exp Med. 2000 Nov;192(3):211-7. Erratum in: Tohoku J Exp Med. 2004 Aug;203(4):359. — View Citation

Galli R, Borello U, Gritti A, Minasi MG, Bjornson C, Coletta M, Mora M, De Angelis MG, Fiocco R, Cossu G, Vescovi AL. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci. 2000 Oct;3(10):986-91. — View Citation

Heslop L, Morgan JE, Partridge TA. Evidence for a myogenic stem cell that is exhausted in dystrophic muscle. J Cell Sci. 2000 Jun;113 ( Pt 12):2299-308. — View Citation

Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012 Jun 14;10(6):709-16. doi: 10.1016/j.stem.2012.05.015. Review. Erratum in: Cell Stem Cell. 2012 Jul 6;11(1):136. — View Citation

Khan MA. Corticosteroid therapy in Duchenne muscular dystrophy. J Neurol Sci. 1993 Dec 1;120(1):8-14. Review. — View Citation

Kojima S, Takagi A, Watanabe T. [Effect of prednisolone on apoptosis and cellular infiltration in mdx mouse muscle]. Rinsho Shinkeigaku. 1999 Nov;39(11):1109-13. Japanese. — View Citation

Lapidos KA, Kakkar R, McNally EM. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res. 2004 Apr 30;94(8):1023-31. Review. — View Citation

Mendell JR, Clark KR. Challenges for gene therapy for muscular dystrophy. Curr Neurol Neurosci Rep. 2006 Jan;6(1):47-56. Review. — View Citation

Mercuri E, Muntoni F. Muscular dystrophies. Lancet. 2013 Mar 9;381(9869):845-60. Review. — View Citation

Nallamilli BR, Ankala A, Hegde M. Molecular diagnosis of Duchenne muscular dystrophy. Curr Protoc Hum Genet. 2014 Oct 1;83:9.25.1-29. doi: 10.1002/0471142905.hg0925s83. — View Citation

Partridge TA. Stem cell therapies for neuromuscular diseases. Acta Neurol Belg. 2004 Dec;104(4):141-7. Review. — View Citation

Price FD, Kuroda K, Rudnicki MA. Stem cell based therapies to treat muscular dystrophy. Biochim Biophys Acta. 2007 Feb;1772(2):272-83. Epub 2006 Sep 6. Review. — View Citation

Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, Mytinger J, Cao B, Gates C, Wernig A, Huard J. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol. 2002 May 27;157(5):851-64. Epub 2002 May 20. — View Citation

Shafritz DA, Oertel M, Menthena A, Nierhoff D, Dabeva MD. Liver stem cells and prospects for liver reconstitution by transplanted cells. Hepatology. 2006 Feb;43(2 Suppl 1):S89-98. Review. — View Citation

Toma JG, Akhavan M, Fernandes KJ, Barnabé-Heider F, Sadikot A, Kaplan DR, Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001 Sep;3(9):778-84. — View Citation

Wang YX, Rudnicki MA. Satellite cells, the engines of muscle repair. Nat Rev Mol Cell Biol. 2011 Dec 21;13(2):127-33. doi: 10.1038/nrm3265. Review. — View Citation

Wong BL, Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J Child Neurol. 2002 Mar;17(3):183-90. Review. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6 Minute Walk Distance (6MWD)	It is used as measure of motor strength in patients with Duchenne Myopathy. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters	6 month