Cloning did not cause Dolly the sheep to get arthritis, scientists confirm

A new study has dismissed concerns that cloning caused early-onset osteoarthritis (OA) in Dolly the sheep.

Scientists from the University of Nottingham and the University of Glasgow have published a radiographic assessment of the skeletons of Dolly, Bonnie (Dolly’s naturally conceived daughter) and Megan and Morag (the first two animals to be cloned from differentiated cells) that shows no abnormal OA.

The study follows the team’s research last year into the Nottingham ‘Dollies’, a quartet of sheep cloned in 2007 from the same line as Dolly, that showed the cloned sheep to age the same as naturally born sheep.

According to their assessment of the skeletons, the OA observed within the skeletons is similar to that naturally conceived sheep and Nottingham’s healthy aged clones.

Professor Sandra Corr, Professor of Small Animal Orthopaedic Surgery who has since moved to Glasgow University, said: “We found that the prevalence and distribution of radiographic-OA was similar to that observed in naturally conceived sheep, and our healthy aged cloned sheep.

As a result we conclude that the original concerns that cloning had caused early-onset OA in Dolly were unfounded.”

The new study arose after the findings regarding the Nottingham ‘Dollies’.

Derived from the same cell line that produced Dolly, the four sheep originated from Professor Keith Campbell’s attempts to improve the efficiency of the cloning method somatic-cell nuclear transfer (SCNT) and were left as his legacy to the University of Nottingham.

Studying the ‘Dollies’, Kevin Sinclair, Professor of Developmental Biology, in the School of Biosciences, along with Corr and David Gardner, Professor of Physiology at Nottingham’s School of Veterinary Medicine and Science, found radiographic evidence of only mild or, in one case, moderate OA.

Images courtesy of the University of Nottingham.

Given that the ‘Dollies’ had aged so apparently normal, the team felt that their findings stood in too stark a contrast to reports that cloning had caused Dolly to suffer from early-onset OA. First emerging in 2003, reports stated that at the age of 5½ Dolly was suffering from OA.

However, the only formal record of any OA in Dolly was a brief mention in a conference abstract, stating that Dolly had OA of the left knee.

In the absence of the original records however, the team were compelled to travel to Edinburgh, where the skeletons are stored in the collections of National Museums Scotland.

With special permission from Dr Andrew Kitchener, Principal Curator of Vertebrates at National Museums Scotland, the team then performed the X-rays on Dolly and her contemporary clones to reassess that 2003 diagnosis.

Sinclair said: “Our findings of last year appeared to be at odds with original concerns surrounding the nature and extent of osteoarthritis in Dolly – who was perceived to have aged prematurely. Yet no formal, comprehensive assessment of osteoarthritis in Dolly was ever undertaken. We therefore felt it necessary to set the record straight.”

US scientists have begun editing genes inside patients to cure a disease that currently requires weekly treatment

For the first time, US scientists have attempted to edit the DNA of cells inside a patient in order to permanently cure a disease that currently requires weekly intravenous therapy.

Scientists at Sangamo Therapeutics are using genome editing to insert a corrective gene into a precise location in the DNA of liver cells.

Ultimately, the doctors aim to enable patients’ livers to produce a lifelong and stable supply of the enzyme iduronate-2-sulfatase (IDS), which sufferers of mucopolysaccharidosis type II (MPS II) – also known as Hunter syndrome – lack.

“For the first time, a patient has received a therapy intended to precisely edit the DNA of cells directly inside the body. We are at the start of a new frontier of genomic medicine,” said Dr. Sandy Macrae, CEO of Sangamo Therapeutics.

To insert the corrective gene the team didn’t use the popularised CRISPR  gene-editing technique, instead they used Sangamo’s zinc finger nuclease (ZFN) genome-editing technology.

In order to restrict editing solely to liver cells, the ZFNs and the corrective gene were delivered in a single intravenous infusion using AAV vectors that target the liver. The ZFNs entered the cells as inactive DNA instructions in a format designed only for liver cells to unlock.

Once “unlocked”, the ZFNs then identified, clung to and cut the DNA in a specific location within the albumin gene. Using the cells’ natural DNA repair processes, liver cells then inserted the corrective gene at the precise location.

“We cut your DNA, open it up, insert a gene, stitch it back up. Invisible mending,” said Macrae in an interview with Medical Xpress, “It becomes part of your DNA and is there for the rest of your life.”

Without IDS people with MPS II suffer debilitating buildup of toxic carbohydrates in cells throughout their body.

As a result, patients may suffer from frequent colds and ear infections, distorted facial features, hearing loss, heart problems, breathing trouble, skin and eye problems, bone and joint flaws, bowel issues and neurological problems.

Previously the treatment for this condition involved weekly infusions of enzyme replacement therapy (ERT), but for patients with MPS II within a day of receiving ERT, IDS can quickly return to near undetectable levels in the blood.

“Even with regular infusions of ERT, which has markedly improved functional health outcomes, patients endure progressive damage to heart, bones and lungs. Many patients with MPS II die of airway obstruction, upper respiratory infection or heart failure before they reach the age of 20,” said Paul Harmatz, M.D., a pediatric gastroenterologist and a principal investigator for the CHAMPIONS study at the UCSF Benioff Children’s Hospital Oakland, where the first subject in the study was treated.