rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies

NCT02710500 | Completed Phase 1 DMC

• 1 other identifier: IRB15-00669
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. A minimum of three subjects will be enrolled into each cohort.

Conditions

Dysferlinopathy

Keywords

LGMD2B; Limb Girdle Muscular Dystrophy; Miyoshi; Gene Transfer; Dysferlin

Outcome Measures

Primary Outcomes (1)

• Determination of safety based on the development of unacceptable toxicity

  Defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity

  2 Years

Secondary Outcomes (4)

• Number of participants showing dysferlin protein expression in muscle tissue

  2 Years

• Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387.

  2 Years

• Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein.

  2 Years

• Number of inflammatory cells in muscle

  2 Years

Study Arms (2)

Cohort 1 (Low Dose)

EXPERIMENTAL

Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 2 x 10\^12 in one muscle. Intervention Drug: rAAVrh.MHCK7.DYSF.DV

Drug: rAAVrh74.MHCK7.DYSF.DV

Cohort 2 (High Dose)

EXPERIMENTAL

Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 6 x 10\^12 vg in one muscle. Intervention Drug: rAAVrh74.MHCK7.DYSF.DV

Drug: rAAVrh74.MHCK7.DYSF.DV

Interventions

rAAVrh74.MHCK7.DYSF.DV DRUG

Biological/Vaccine: rAAVrh74.MHCK7.DYSF.DV Recombinant adeno-associated virus carrying a dysferlin transgene under control of a muscle specific MHCK7 promoter.

Cohort 1 (Low Dose); Cohort 2 (High Dose)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
• Established mutations of the dysferlin gene on both alleles
• Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
• Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).

You may not qualify if:

• Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
• The presence of a Dysferlin mutations without weakness or loss of function
• Symptoms or signs of cardiomyopathy, including:
• Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
• Echocardiogram with ejection fraction below 40%
• Diagnosis of (or ongoing treatment for) an autoimmune disease
• Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count \< 1.5K/µL
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
• Pregnancy
• AAVrh74 or AAV8 binding antibody titers \> 1:50 as determined by ELISA immunoassay
• Abnormal laboratory values in the clinically significant range in the table below, based upon normal values in the Nationwide Children's Hospital Laboratory: GGT, Total Bilirubin, Cystatine, Hemoglobin, White Blood Cells

Sponsors & Collaborators

• Sarepta Therapeutics, Inc.: lead

Study Sites (1)

Nationwide Children's Hosptial

Columbus, Ohio, 43205, United States

Location

Related Publications (2)

• Sondergaard PC, Griffin DA, Pozsgai ER, Johnson RW, Grose WE, Heller KN, Shontz KM, Montgomery CL, Liu J, Clark KR, Sahenk Z, Mendell JR, Rodino-Klapac LR. AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. Ann Clin Transl Neurol. 2015 Mar;2(3):256-70. doi: 10.1002/acn3.172. Epub 2015 Jan 20.

  PMID: 25815352 BACKGROUND

• Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One. 2012;7(6):e39233. doi: 10.1371/journal.pone.0039233. Epub 2012 Jun 15.

  PMID: 22720081 BACKGROUND

Related Links

• Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital

MeSH Terms

Conditions

Dysferlinopathy; Limb-girdle muscular dystrophy, type 2B; Muscular Dystrophies, Limb-Girdle

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Jerry R Mendell, MD

  Director, Center for Gene Therapy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2016
• First Posted: March 16, 2016
• Study Start: March 1, 2016
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: May 13, 2021

Record last verified: 2021-05

Locations

US (1)